Substituted Aniline Derivatives

ABSTRACT

The present invention relates to novel aniline derivatives and their use in therapy, in particular their use in the treatment of fungal infections.

CROSS-REFERENCE

This application claims the benefit under 35 U.S.C. §121 of co-pendingU.S. application Ser. No. 11/782,337 filed Jul. 24, 2007 which is herebyincorporated by reference in its entirety, and which claims the right ofpriority under 35 USC §119 (a)-(d) of GB 0614678.1, filed Jul. 24, 2006;GB 0614677.3, filed Jul. 24, 2006; GB 0704645.1, filed Mar. 9, 2007; andGB 0704648.5, filed Mar. 9, 2007, each of which is incorporated byreference herein in its entirety.

BACKGROUND OF THE INVENTION

Many different species of fungi live harmlessly on the skin and insidethe body of all animals including humans. However under certaincircumstances, often as a result of a weakened or suppressed immunesystem, individuals will succumb to opportunistic fungal infections. Theinfections may be superficial or systemic. Superficial infections suchas athletes' foot, ringworm and thrush are generally caused bypathogenic fungi. They are slow to develop, often remaining asymptomaticfor many years, and are generally well tolerated or treated. Systemicinfections are caused by primary and opportunistic fungi. They developrapidly in susceptible hosts and hence require rapid treatment, oftenbefore diagnosis and tend to be associated with a poor prognosis. Theseusually occur in hospitalized patients.

The incidence of life-threatening fungal infections has increaseddramatically as the population of immunocompromised individuals(including cancer, organ transplant and AIDS patients) has increased. Asa result it is the cause of an increasing financial and logistic burdenon the medical care system and its providers.

To date a number of different targets and metabolic pathways have beenexploited clinically to kill fungi or inhibit their growth. The mostrecent approach to emerge targets the organisms' need to synthesiseglucan. Glucan, in particular β-1,3-D-glucan, is essential to theintegrity of the cell wall of a wide range of fungi, in particular theCandida and Aspergillus species. The main enzyme activity responsiblefor glucan synthesis within fungi is 1,3-β-D-glucan synthase. Inhibitorsof this activity prevent the synthesis of glucan and thereby compromisethe integrity of the cell wall, leading to destruction of the cell.

A class of compounds called echinocandins are known to act as glucansynthase inhibitors and include caspofungin acetate, micafungin andanidulafungin. The chemical structure of caspofungin acetate is shownbelow. The other echinocandin compounds have very similar structures.

Although the echinocandins have met some success in their antifungalaction, it would be desirable to provide compounds that providecomparable glucan synthase inhibition and which have improvedpharmacokinetic properties and which are relatively small organicmolecules which are easier to manufacture.

SUMMARY OF THE INVENTION

Provided herein are compounds that are useful as antifungal agents. Alsoprovided are pharmaceutical compositions that include such antifungalagents. Also provided herein are methods of using such compounds for thetreatment of diseases, disorders or conditions caused, exacerbated, orotherwise induced or related to fungi.

Provided herein are compounds or pharmaceutically acceptable salts ofFormula I:

wherein,

-   -   n is 0, 1, or 2;    -   R₁ and R₂ are independently selected from H, (C₁-C₆)alkyl,        (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₁-C₆)heteroalkyl,        (C₁-C₆)heteroalkenyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl,        (C₃-C₈)heterocycloalkyl, (C₃-C₈)heterocycloalkenyl, aryl, and        heteroaryl, any of which is optionally substituted with 1 or 2        independently selected R_(x) groups;        -   or R₁ and R₂ together with the nitrogen atom to which they            are attached form a 4- to 8-membered heterocycloalkyl or            heterocycloalkenyl group, any of which is optionally            substituted with 1 or 2 independently selected R_(x) groups;    -   Ar is selected from phenyl, naphthyl, and a monocylic or        bicyclic heteroaryl group, any of which is optionally        substituted with 1 or 2 independently selected R_(x) groups, or        with a phenyl, O-phenyl, or OCH₂-phenyl in which the phenyl        group is further optionally substituted with 1 or 2        independently selected R_(x) groups;    -   R₃ is L₁-L₂-R₄, where L₁ is selected from a bond, O, NR₁, and S;        L₂ is selected from a bond, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,        (C₁-C₆)alkynyl, (C₁-C₆)heteroalkyl, (C₁-C₆)heteroalkenyl,        (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, (C₃-C₈)heterocycloalkyl,        and (C₃-C₈)heterocycloalkenyl;        -   and R₄ is selected from H, cycloalkyl, cycloalkenyl,            heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl,            any of which is optionally substituted with 1 or 2            independently selected R_(x) groups;        -   R_(x) is be L_(s1)L_(s2)R_(s), wherein each L_(s1) and            L_(s2) is independently selected from a bond, —O—, —C(═O)—,            —S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—,            —NHS(═O)₂, —OC(O)NH—, —NHC(O)O—, (C₁-C₆) alkyl, and —(C₂-C₆)            alkenyl; and R_(s) is selected from hydrogen, alkyl,            cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,            alkoxy, aryloxy, mercapto, alkylthio, arylthio,            alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,            cyano, halo, isocyanato, thiocyanato, isothiocyanato, nitro,            perhaloalkyl, perfluoroalkyl, silyl, and amino, including            mono- and di-substituted amino groups, and the protected            derivatives thereof;

or a pharmaceutically acceptable salt, prodrug, solvate, polymorph,tautomer, or isomer thereof;

or an active metabolite thereof.

Provided herein are compounds or pharmaceutically acceptable salts ofFormula II:

wherein:

-   -   n is 0 or 1,    -   R₅ is selected from halogen, C₁-C₆ alkyl, hydroxy, —O(C₁-C₆        alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆ alkyl),        —(C₁-C₆ haloalkyl), —NHCOH, —NHCO(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)COH, —N(C₁-C₆ alkyl)CO(C₁-C₆ alkyl), —NHSO₂H, —NHSO₂(C₁-C₆        alkyl), —N(C₁-C₆ alkyl)SO₂H, —N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl),        —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, and SO₂(C₁-C₆        alkyl),

or a pharmaceutically acceptable salt, prodrug, solvate, polymorph,tautomer, or isomer thereof.

Provided herein are compounds or pharmaceutically acceptable salts ofFormula III:

wherein:

-   -   n is 0 or 1;    -   R₅ is selected from hydrogen, halogen, C₁-C₆ alkyl, hydroxy,        —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆        alkyl), —(C₁-C₆ haloalkyl), —NHCOH, —NHCO(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)COH, —N(C₁-C₆ alkyl)CO(C₁-C₆ alkyl), —NHSO₂H, —NHSO₂(C₁-C₆        alkyl), —N(C₁-C₆ alkyl)SO₂H, —N(C₁-C₆ alkyl) SO₂(C₁-C₆ alkyl),        —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, and SO₂(C₁-C₆        alkyl); and    -   R₆ is selected from hydrogen, halogen and a C₁-C₆ alkyl, phenyl,        —O-phenyl, or —O-benzyl group optionally substituted with        halogen, C₁-C₆ alkyl, hydroxy, —O(C₁-C₆ alkyl), —CO₂H, or        —CO₂(C₁-C₆ alkyl),

or a pharmaceutically acceptable salt, prodrug, solvate, polymorph,tautomer, or isomer thereof.

Provided herein are compounds or pharmaceutically acceptable salts ofFormula IV or Formula V:

wherein:

-   -   R₇ is hydrogen, halogen, or C₁-C₆ alkyl; and    -   R₈ is a phenyl group optionally substituted with one or two        groups independently selected from halogen, C₁-C₆ alkyl,        hydroxy, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —NHCOH, —NHCO(C₁-C₆        alkyl), —N(C₁-C₆ alkyl)COH, —N(C₁-C₆ alkyl)CO(C₁-C₆ alkyl),        —NHSO₂H, —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂H, —N(C₁-C₆        alkyl) SO₂(C₁-C₆ alkyl), —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆        alkyl)₂, and SO₂(C₁-C₆ alkyl),

or a pharmaceutically acceptable salt, prodrug, solvate, polymorph,tautomer, or isomer thereof.

Provided herein are compounds or pharmaceutically acceptable salts ofFormula VI or Formula VII:

wherein:

-   -   R₆ is selected from hydrogen, halogen and a C₁-C₆ alkyl, phenyl,        —O-phenyl, or —O-benzyl group optionally substituted with        halogen, C₁-C₆ alkyl, hydroxy, —O(C₁-C₆ alkyl), —CO₂H, or        —CO₂(C₁-C₆ alkyl);    -   R₇ is hydrogen, halogen, or C₁-C₆ alkyl; and    -   R₈ is a phenyl group optionally substituted with one or two        groups independently selected from halogen, C₁-C₆ alkyl,        hydroxy, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —NHCOH, —NHCO(C₁-C₆        alkyl), —N(C₁-C₆ alkyl)COH, —N(C₁-C₆ alkyl)CO(C₁-C₆ alkyl),        —NHSO₂H, —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂H, —N(C₁-C₆        alkyl) SO₂(C₁-C₆ alkyl), —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆        alkyl)₂, and SO₂(C₁-C₆ alkyl),

or a pharmaceutically acceptable salt, prodrug, solvate, polymorph,tautomer, or isomer thereof.

In some embodiments, R₁ and R₂, together with the nitrogen atom to whichthey are attached form a heterocycloalkyl group selected from:

wherein:

-   -   each NH₂ group is optionally substituted with a C₁-C₆ alkyl        group;    -   X is O, NR or SO₂, and    -   each R is independently selected from halogen, —OH, —NH₂, —SH,        —S(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, C₁-C₆        alkyl, C₁-C₆ haloalkyl, and C₁-C₆ heteroalkyl.

In some embodiments, R is independently selected from hydrogen and C₁-C₆alkyl.

In some embodiments, at least one NH₂ group is unsubstituted. In otherembodiments, each NH₂ group is unsubstituted.

In some embodiments, R₁ and R₂, together with the nitrogen atom to whichthey are attached

form a heterocycloalkyl group selected from

In some embodiments, Ar is a phenyl, pyridyl or pyrimidyl group. In someembodiments, Ar is a phenyl, pyridyl or pyrimidyl group optionallysubstituted with one or two substituents independently selected fromhalogen and a C₁-C₆ alkyl, phenyl, —O-phenyl, or —O-benzyl groupoptionally substituted with halogen, C₁-C₆ alkyl, hydroxy, —O(C₁-C₆alkyl), —CO₂H, or —CO₂(C₁-C₆ alkyl). In some embodiments, Ar is a phenylgroup optionally substituted with one or two substituents independentlyselected from halogen and a C₁-C₆ alkyl, phenyl, —O-phenyl, or —O-benzylgroup optionally substituted with halogen, C₁-C₆ alkyl, hydroxy,—O(C₁-C₆ alkyl), —CO₂H, or —CO₂(C₁-C₆ alkyl).

In some embodiments, R₁ is hydrogen, —NH₂, —OH, —SH, —N(C₁-C₃ alkyl)₂,—NH(C₁-C₃ alkyl), —NCO₂(C₁-C₃ alkyl), —NCO₂H, —NCONH₂,

In some embodiments, R₂ is hydrogen, halogen, or a group selected fromphenyl, O-phenyl, and O—CH₂-phenyl, optionally substituted with halogenC₁-C₆ alkyl, —OH, —COOH, —COO(C₁-C₆ alkyl). In some embodiments, R₂ ishydrogen.

In some embodiments, R₄ is a phenyl group optionally substituted withone or two groups independently selected from halogen, C₁-C₆ alkyl,hydroxy, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆alkyl), —(C₁-C₆ haloalkyl), —NHCOH, —NHCO(C₁-C₆ alkyl), —N(C₁-C₆alkyl)COH, —N(C₁-C₆ alkyl)CO(C₁-C₆ alkyl), —NHSO₂H, —NHSO₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)SO₂H, —N(C₁-C₆ alkyl) SO₂(C₁-C₆ alkyl), —CONH₂,—CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, and SO₂(C₁-C₆ alkyl).

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) may possess one or more stereocentersand each center may exist in the R or S configuration, or combinationsthereof. Likewise, the compounds presented herein may possess one ormore double bonds and each may exist in the E (trans) or Z (cis)configuration, or combinations thereof. Presentation of one particularstereoisomer, regioisomer, diastereomer, enantiomer or epimer should beunderstood to include all possible stereoisomers, regioisomers,diastereomers, enantiomers or epimers and mixtures thereof. Thus, thecompounds presented herein include all separate configurationalstereoisomeric, regioisomeric, diastereomeric, enantiomeric, andepimeric forms as well as the corresponding mixtures thereof. Thecompounds presented herein include racemic mixtures, in all ratios, ofstereoisomeric, regioisomeric, diastereomeric, enantiomeric, andepimeric forms. Techniques for inverting or leaving unchanged aparticular stereocenter, and those for resolving mixtures ofstereoisomers, or racemic mixtures, are well known in the art and it iswell within the ability of one of skill in the art to choose anappropriate method for a particular situation. See, for example, Furnisset al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991,809-816; and Heller, Acc. Chem. Res. 1990, 23, 128.

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) may exist as tautomers. Tautomers arecompounds that are interconvertible by migration of a hydrogen atom,accompanied by a switch of a single bond and adjacent double bond. Insolutions where tautomerization is possible, a chemical equilibrium ofthe tautomers will exist. The exact ratio of the tautomers depends onseveral factors, including temperature, solvent, and pH. Some examplesof tautomeric pairs include:

In some embodiments, the compounds of Formula I (including withoutlimitation any of the compounds specifically or generically describedherein, including the compounds presented in the tables) are useful asanti-fungal agents meaning that they kill and/or inhibit the growth offungi. Thus, the compounds described herein may be used in medicine andare particularly useful as antifungal agents. The compounds describedherein are thought to derive their activity from the inhibition of thesynthesis of β-1,3-D-glucan. The compounds have advantages over theknown glucan synthase inhibitors such as those belonging to theechinocandin family. For example, the existing inhibitors are modifiednatural products which are limited in their use by poor pharmacokineticproperties. In contrast the compounds described herein are inhibitors ofβ-1,3-glucan synthase, they are readily synthesised by standardchemistry, and they have more drug-like properties that are compatiblewith oral bioavailability. The compounds described herein are activeagainst a wide range of fungi, particularly Candida such as Candidaalbicans and Aspergillus such as Aspergillus fumigatus.

In a second aspect is a compound according to the first aspect describedherein for therapeutic use.

A third aspect described herein is a pharmaceutical compositioncomprising a compound according to the first aspect described herein anda pharmaceutically acceptable diluent or carrier.

A fourth aspect described herein is the use of a compound according tothe first aspect described herein for the manufacture of a medicamentfor the treatment of a fungal infection.

In a fifth aspect is a method for the treatment of a fungal infectionwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to the first aspect describedherein.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredin a single dose; (ii) the time between multiple administrations isevery 6 hours; (iii) the compound is administered to the mammal every 8hours. In further or alternative embodiments, the method comprises adrug holiday, wherein the administration of the compound is temporarilysuspended or the dose of the compound being administered is temporarilyreduced; at the end of the drug holiday, dosing of the compound isresumed. The length of the drug holiday can vary from 2 days to 1 year.

Provided herein are methods for using a compound of Formula I, for themanufacture of a medicament for the treatment of a fungal infection. Insome embodiments, the fungal infection is caused by a strain of Candidaor Aspergillus.

Provided herein are pharmaceutical compositions comprising a compound ofFormula I and a pharmaceutically acceptable diluent or carrier.

Provided herein are methods for treating a subject at risk of orsuffering from a fungal infection, the method comprising administeringto the subject a composition comprising a therapeutically effectiveamount of the compound of Formula I. In some embodiments, the compoundof Formula I has an IC₅₀ of the compound for C. albicans growth is about8 μM to about 55 μM. In some embodiments, the IC₅₀ of the compound forA. fumigatus growth is about 4 μM to about 93 μM In some embodiments,the IC₅₀ of the compound for biosynthesis of glucan in C. albicans isabout 3 μM to about 34 μM. In some embodiments, the IC₅₀ of the compoundfor biosynthesis of glucan in A. fumigatus is about 4 μM to about 93 μM.

Provided herein are methods of administering a therapeutically effectiveamount of a supplemental antifungal compound. In some embodiments, thesupplemental antifungal compound is anidulafungin, caspofungin,micafungin, natamycin, rimocidin, nystatin, amphotericin B, miconazole,ketoconazole, clotrimazole, econazole, bifonazole, butoconazole,fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole,tioconazole, triazole, fluconazole, itraconazole, isavuconazoleravuconazole, posaconazole, voriconazole, terconazole, terbinafine,amorolfine, naftifine, butenafine, ciclopirox olamine, 5-fluorocytosine,gentian violet, haloprogin, tolnaftate, or undecylenic acid.

In some embodiments, the compound and the supplemental antifungalcompound are administered through separate routes of administration.

In some embodiments, the subject is diagnosed as suffering fromblastomycosis, tinea, coccidiomycosis, cryptococcosis, candidiasis,moniliasis, dermatomycosis, dermatophytosis, favus, keratomycosis,phycomycosis, sporotrichosis, or rhinosporidiosis.

In some embodiments, subject is immunocompromised. In some embodiments,the subject is suffering from AIDS, cancer, severe combinedimmunodefficiency, tuberculosis, diabetes, intravenous drug abuse, orsevere burns. In some embodiemnts, the subject is undergoingimmunosuppressive therapy.

In some embodiments, the subject is exposed to a chronic antibiotic,chronic corticosteroid treatment, undergoes prolonged use of anintravenous catheter, or undergoes prolonged use of a urinary catheter.

In some embodiments, the methods comprise further administering to thesubject a composition comprising a therapeutically effective amount ofan immunosuppressive agent. In some embodiments, the methods comprisefurther administering a chemotherapy agent. In some embodiments, themethods comprise further administering an anti-inflammatory agent. Insome embodiments, the methods comprise further administering a bacterialantibiotic compound. In some embodiments, the methods comprise furtheradministering an anti-HIV compound. In some embodiments, the methodscomprise further administering an anti-diabetic agent.

In some embodiments, the administration is oral, topical, transdermal,intravenous, subcutaneous, intracutaneous, intramuscular, intranasal,rectal, vaginal, buccal, or sublingual. In some embodiments, thecomposition is administered as a cream, ointment, paste, gel, spray, ora liposomal preparation.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features described herein are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles described herein are utilized, and theaccompanying drawings of which:

FIG. 1 shows the inhibition of glucose incorporation into β-1,3-D-glucanin Candida Albicans strain CAF2-1. OGT4154 preferentially inhibitsβ-1,3-D-glucan biosynthesis in Candida Albicans.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments described herein may beemployed in practicing the invention. It is intended that the claimsdefine the scope of the invention and that methods and structures withinthe scope of these claims and their equivalents be covered thereby.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, without limitation, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

Certain Chemical Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. In the event that thereis a plurality of definitions for terms herein, those in this sectionprevail. Where reference is made to a URL or other such identifier oraddress, it is understood that such identifiers can change andparticular information on the internet can come and go, but equivalentinformation can be found by searching the internet or other appropriatereference source. Reference thereto evidences the availability andpublic dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an” and “the” include pluralreferents unless the context clearly dictates otherwise. It should alsobe noted that use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes”, and “included” is not limiting.

Definition of standard chemistry terms may be found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, IR andUV/Vis spectroscopy and pharmacology, within the skill of the art areemployed. Unless specific definitions are provided, the nomenclatureemployed in connection with, and the laboratory procedures andtechniques of, analytical chemistry, synthetic organic chemistry, andmedicinal and pharmaceutical chemistry described herein are those knownin the art. Standard techniques can be used for chemical syntheses,chemical analyses, pharmaceutical preparation, formulation, anddelivery, and treatment of patients. Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods well known in the art and as describedin various general and more specific references that are cited anddiscussed throughout the present specification. Throughout thespecification, groups and substituents thereof can be chosen by oneskilled in the field to provide stable moieties and compounds.

Where substituent groups are specified by their conventional chemicalformulas, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left. As a non-limiting example, —CH₂O— isequivalent to —OCH₂—.

Unless otherwise noted, the use of general chemical terms, such asthough not limited to “alkyl,” “amine,” “aryl,” are equivalent to theiroptionally substituted forms. For example, “alkyl,” as used herein,includes optionally substituted alkyl.

The terms “moiety”, “chemical moiety”, “group” and “chemical group”, asused herein refer to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined below.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible. Thus, any substituentsdescribed should generally be understood as having a maximum molecularweight of about 1,000 daltons, and more typically, up to about 500daltons (except in those instances where macromolecular substituents areclearly intended, e.g., polypeptides, polysaccharides, polyethyleneglycols, DNA, RNA and the like).

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as theranges C₁-C₂ and C₁-C₃. Thus, by way of example only, “C₁-C₄ alkyl”indicates that there are one to four carbon atoms in the alkyl group,i.e., the alkyl group is selected from among methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Whenever itappears herein, a numerical range such as “1 to 10” refers to eachinteger in the given range; e.g., “1 to 10 carbon atoms” means that thegroup may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbonatoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9carbon atoms, or 10 carbon atoms.

The term “hydrocarbon” as used herein, alone or in combination, refersto a compound or chemical group containing only carbon and hydrogenatoms.

The terms “heteroatom” or “hetero” as used herein, alone or incombination, refer to an atom other than carbon or hydrogen. Heteroatomsare may be independently selected from among oxygen, nitrogen, sulfur,phosphorous, silicon, selenium and tin but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can be the same as each another, or some or allof the two or more heteroatoms can each be different from the others.

The term “alkyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain, or optionally substitutedbranched-chain saturated hydrocarbon monoradical having from one toabout ten carbon atoms, more preferably one to six carbon atoms.Examples include, but are not limited to methyl, ethyl, n-propyl,isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyland hexyl, and longer alkyl groups, such as heptyl, octyl and the like.Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl” or“C₁₋₆ alkyl”, means that the alkyl group may consist of 1 carbon atom, 2carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbonatoms, although the present definition also covers the occurrence of theterm “alkyl” where no numerical range is designated.

The term “alkenyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain, or optionally substitutedbranched-chain hydrocarbon monoradical having one or more carbon-carbondouble-bonds and having from two to about ten carbon atoms, morepreferably two to about six carbon atoms. The group may be in either thecis or trans conformation about the double bond(s), and should beunderstood to include both isomers. Examples include, but are notlimited to ethenyl (—CH═CH₂), propenyl (—CH₂CH═CH₂), isopropenyl[—C(CH₃)═CH₂], butenyl, 1,3-butadienyl and the like. Whenever it appearsherein, a numerical range such as “C₂-C₆ alkenyl” or “C₂₋₆ alkenyl”,means that the alkenyl group may consist of 2 carbon atoms, 3 carbonatoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although thepresent definition also covers the occurrence of the term “alkenyl”where no numerical range is designated.

The term “alkynyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain or optionally substitutedbranched-chain hydrocarbon monoradical having one or more carbon-carbontriple-bonds and having from two to about ten carbon atoms, morepreferably from two to about six carbon atoms. Examples include, but arenot limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and thelike. Whenever it appears herein, a numerical range such as “C₂-C₆alkynyl” or “C₂₋₆ alkynyl”, means that the alkynyl group may consist of2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6carbon atoms, although the present definition also covers the occurrenceof the term “alkynyl” where no numerical range is designated.

The term “aliphatic” as used herein, alone or in combination, refers toan optionally substituted, straight-chain or branched-chain, non-cyclic,saturated, partially unsaturated, or fully unsaturated nonaromatichydrocarbon. Thus, the term collectively includes alkyl, alkenyl andalkynyl groups.

The terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” as usedherein, alone or in combination, refer to optionally substituted alkyl,alkenyl and alkynyl structures respectively, as described above, inwhich one or more of the skeletal chain carbon atoms (and any associatedhydrogen atoms, as appropriate) are each independently replaced with aheteroatom (i.e. an atom other than carbon, such as though not limitedto oxygen, nitrogen, sulfur, silicon, phosphorous, tin or combinationsthereof), or heteroatomic group such as though not limited to —O—O—,—S—S—, —O—S—, —S—O—, ═N—N═, —N═N—, —N═N—NH—, —P(O)₂—, —O—P(O)₂—,—P(O)₂—O—, —S(O)—, —S(O)₂—, —SnH₂— and the like.

The terms “haloalkyl”, “haloalkenyl” and “haloalkynyl” as used herein,alone or in combination, refer to optionally substituted alkyl, alkenyland alkynyl groups respectively, as defined above, in which one or morehydrogen atoms is replaced by fluorine, chlorine, bromine or iodineatoms, or combinations thereof. In some embodiments two or more hydrogenatoms may be replaced with halogen atoms that are the same as eachanother (e.g. difluoromethyl); in other embodiments two or more hydrogenatoms may be replaced with halogen atoms that are not all the same aseach other (e.g. 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examplesof haloalkyl groups are fluoromethyl and bromoethyl. A non-limitingexample of a haloalkenyl group is bromoethenyl. A non-limiting exampleof a haloalkynyl group is chloroethynyl.

The terms “cycle”, “cyclic”, “ring” and “membered ring” as used herein,alone or in combination, refer to any covalently closed structure,including alicyclic, heterocyclic, aromatic, heteroaromatic andpolycyclic fused or non-fused ring systems as described herein. Ringscan be optionally substituted. Rings can form part of a fused ringsystem. The term “membered” is meant to denote the number of skeletalatoms that constitute the ring. Thus, by way of example only,cyclohexane, pyridine, pyran and pyrimidine are six-membered rings andcyclopentane, pyrrole, tetrahydrofuran and thiophene are five-memberedrings.

The term “fused” as used herein, alone or in combination, refers tocyclic structures in which two or more rings share one or more bonds.

The term “cycloalkyl” as used herein, alone or in combination, refers toan optionally substituted, saturated, hydrocarbon monoradical ring,containing from three to about fifteen ring carbon atoms or from threeto about ten ring carbon atoms, though may include additional, non-ringcarbon atoms as substituents (e.g. methylcyclopropyl). Whenever itappears herein, a numerical range such as “C₃-C₆ cycloalkyl” or “C₃₋₆cycloalkyl”, means that the cycloalkyl group may consist of 3 carbonatoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, i.e., iscyclopropyl, cyclobutyl, cyclopentyl or cyclohepty, although the presentdefinition also covers the occurrence of the term “cycloalkyl” where nonumerical range is designated. The term includes fused, non-fused,bridged and spiro radicals. A fused cycloalkyl may contain from two tofour fused rings where the ring of attachment is a cycloalkyl ring, andthe other individual rings may be alicyclic, heterocyclic, aromatic,heteroaromatic or any combination thereof. Examples include, but are notlimited to cyclopropyl, cyclopentyl, cyclohexyl, decalinyl, andbicyclo[2.2.1]heptyl and adamantyl ring systems. Illustrative examplesinclude, but are not limited to the following moieties:

and the like.

The term “cycloalkenyl” as used herein, alone or in combination, refersto an optionally substituted hydrocarbon non-aromatic, monoradical ring,having one or more carbon-carbon double-bonds and from three to abouttwenty ring carbon atoms, three to about twelve ring carbon atoms, orfrom three to about ten ring carbon atoms. The term includes fused,non-fused, bridged and spiro radicals. A fused cycloalkenyl may containfrom two to four fused rings where the ring of attachment is acycloalkenyl ring, and the other individual rings may be alicyclic,heterocyclic, aromatic, heteroaromatic or any combination thereof. Fusedring systems may be fused across a bond that is a carbon-carbon singlebond or a carbon-carbon double bond. Examples of cycloalkenyls include,but are not limited to cyclohexenyl, cyclopentadienyl andbicyclo[2.2.1]hept-2-ene ring systems. Illustrative examples include,but are not limited to the following moieties:

and the like.

The term “heterocycloalkyl” as used herein, alone or in combination,refer to optionally substituted, saturated, partially unsaturated orfully unsaturated nonaromatic ring monoradicals containing from three toabout twenty ring atoms, where one or more of the ring atoms are an atomother than carbon, independently selected from among oxygen, nitrogen,sulfur, phosphorous, silicon, selenium and tin but are not limited tothese atoms. In embodiments in which two or more heteroatoms are presentin the ring, the two or more heteroatoms can be the same as eachanother, or some or all of the two or more heteroatoms can each bedifferent from the others. The terms include fused, non-fused, bridgedand spiro radicals. A fused non-aromatic heterocyclic radical maycontain from two to four fused rings where the attaching ring is anon-aromatic heterocycle, and the other individual rings may bealicyclic, heterocyclic, aromatic, heteroaromatic or any combinationthereof. Fused ring systems may be fused across a single bond or adouble bond, as well as across bonds that are carbon-carbon,carbon-hetero atom or hetero atom-hetero atom. The terms also includeradicals having from three to about twelve skeletal ring atoms, as wellas those having from three to about ten skeletal ring atoms. Attachmentof a non-aromatic heterocyclic subunit to its parent molecule can be viaa heteroatom or a carbon atom. Likewise, additional substitution can bevia a heteroatom or a carbon atom. The terms also include all ring formsof the carbohydrates, including but not limited to the monosaccharides,the disaccharides and the oligosaccharides. As a non-limiting example,an imidazolidine non-aromatic heterocycle may be attached to a parentmolecule via either of its N atoms (imidazolidin-1-yl orimidazolidin-3-yl) or any of its carbon atoms (imidazolidin-2-yl,imidazolidin-4-yl or imidazolidin-5-yl). In certain embodiments,non-aromatic heterocycles contain one or more carbonyl or thiocarbonylgroups such as, for example, oxo- and thio-containing groups. Examplesinclude, but are not limited to pyrrolidinyl, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Illustrative examples of heterocycloalkyl groups, alsoreferred to as non-aromatic heterocycles, include:

and the like.

The term “aromatic” as used herein, refers to a planar, cyclic orpolycyclic, ring moiety having a delocalized π-electron systemcontaining 4n+2π electrons, where n is an integer. Aromatic rings can beformed by five, six, seven, eight, nine, or more than nine atoms.Aromatics can be optionally substituted and can be monocyclic orfused-ring polycyclic. The term aromatic encompasses both all carboncontaining rings (e.g., phenyl) and those rings containing one or moreheteroatoms (e.g., pyridine).

The term “aryl” as used herein, alone or in combination, refers to anoptionally substituted aromatic hydrocarbon radical of six to abouttwenty ring carbon atoms, and includes fused and non-fused aryl rings. Afused aryl ring radical contains from two to four fused rings where thering of attachment is an aryl ring, and the other individual rings maybe alicyclic, heterocyclic, aromatic, heteroaromatic or any combinationthereof. Further, the term aryl includes fused and non-fused ringscontaining from six to about twelve ring carbon atoms, as well as thosecontaining from six to about ten ring carbon atoms. A non-limitingexample of a single ring aryl group includes phenyl; a fused ring arylgroup includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and anon-fused bi-aryl group includes biphenyl.

The term “heteroaryl” as used herein, alone or in combination, refers tooptionally substituted aromatic monoradicals containing from about fiveto about twenty skeletal ring atoms, where one or more of the ring atomsis a heteroatom independently selected from among oxygen, nitrogen,sulfur, phosphorous, silicon, selenium and tin but not limited to theseatoms and with the proviso that the ring of said group does not containtwo adjacent O or S atoms. In embodiments in which two or moreheteroatoms are present in the ring, the two or more heteroatoms can bethe same as each another, or some or all of the two or more heteroatomscan each be different from the others. The term heteroaryl includesoptionally substituted fused and non-fused heteroaryl radicals having atleast one heteroatom. The term heteroaryl also includes fused andnon-fused heteroaryls having from five to about twelve skeletal ringatoms, as well as those having from five to about ten skeletal ringatoms. Bonding to a heteroaryl group can be via a carbon atom or aheteroatom. Thus, as a non-limiting example, an imidiazole group may beattached to a parent molecule via any of its carbon atoms(imidazol-2-yl, imidazol-4-yl or imidazol-5-yl), or its nitrogen atoms(imidazol-1-yl or imidazol-3-yl). Likewise, a heteroaryl group may befurther substituted via any or all of its carbon atoms, and/or any orall of its heteroatoms. A fused heteroaryl radical may contain from twoto four fused rings where the ring of attachment is a heteroaromaticring and the other individual rings may be alicyclic, heterocyclic,aromatic, heteroaromatic or any combination thereof. A non-limitingexample of a single ring heteroaryl group includes pyridyl; fused ringheteroaryl groups include benzimidazolyl, quinolinyl, acridinyl; and anon-fused bi-heteroaryl group includes bipyridinyl. Further examples ofheteroaryls include, without limitation, furanyl, thienyl, oxazolyl,acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl,benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl,indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl,pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl,purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl,quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, thiadiazolyland the like, and their oxides, such as for example pyridyl-N-oxide.Illustrative examples of heteroaryl groups include the followingmoieties:

and the like.

The terms “halogen”, “halo” or “halide” as used herein, alone or incombination refer to fluoro, chloro, bromo and iodo.

The term “hydroxy” as used herein, alone or in combination, refers tothe monoradical —OH.

The term “cyano” as used herein, alone or in combination, refers to themonoradical —CN.

The term “nitro” as used herein, alone or in combination, refers to themonoradical —NO₂.

The term “oxy” as used herein, alone or in combination, refers to thediradical —O—.

The term “oxo” as used herein, alone or in combination, refers to thediradical ═O.

The term “carbonyl” as used herein, alone or in combination, refers tothe diradical —C(═O)—, which may also be written as —C(O)—.

The terms “carboxy” or “carboxyl” as used herein, alone or incombination, refer to the moiety —C(O)OH, which may also be written as—COOH.

The term “alkoxy” as used herein, alone or in combination, refers to analkyl ether radical, —O-alkyl, including the groups —O-aliphatic and—O-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups maybe optionally substituted, and wherein the terms alkyl, aliphatic andcarbocyclyl are as defined herein. Non-limiting examples of alkoxyradicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “sulfinyl” as used herein, alone or in combination, refers tothe diradical —S(═O)—.

The term “sulfonyl” as used herein, alone or in combination, refers tothe diradical —S(═O)₂—.

The terms “sulfonamide”, “sulfonamido” and “sulfonamidyl” as usedherein, alone or in combination, refer to the diradical groups—S(═O)₂—NH— and —NH—S(═O)₂—.

The terms “sulfamide”, “sulfamido” and “sulfamidyl” as used herein,alone or in combination, refer to the diradical group —NH—S(═O)₂—NH—.

Certain Pharmaceutical Terminology

The term “subject”, “patient” or “individual” as used herein inreference to individuals suffering from a disorder, and the like,encompasses mammals and non-mammals. Examples of mammals include, butare not limited to, any member of the Mammalian class: humans, non-humanprimates such as chimpanzees, and other apes and monkey species; farmanimals such as cattle, horses, sheep, goats, swine; domestic animalssuch as rabbits, dogs, and cats; laboratory animals including rodents,such as rats, mice and guinea pigs, and the like. Examples ofnon-mammals include, but are not limited to, birds, fish and the like.In one embodiment of the methods and compositions provided herein, themammal is a human.

The terms “treat,” “treating” or “treatment,” and other grammaticalequivalents as used herein, include alleviating, abating or amelioratinga disease or condition symptoms, preventing additional symptoms,ameliorating or preventing the underlying metabolic causes of symptoms,inhibiting the disease or condition, e.g., arresting the development ofthe disease or condition, relieving the disease or condition, causingregression of the disease or condition, relieving a condition caused bythe disease or condition, or stopping the symptoms of the disease orcondition, and are intended to include prophylaxis. The terms furtherinclude achieving a therapeutic benefit and/or a prophylactic benefit.By therapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

Where combination treatments are contemplated, it is not intended thatthe compounds described herein be limited by the particular nature ofthe combination. For example, the compounds described herein may beadministered in combination as simple mixtures as well as a chemicalhybrids. An example of the latter is where the compound is covalentlylinked to a targeting carrier or to an active pharmaceutical. Covalentbinding can be accomplished in many ways, such as, though not limitedto, the use of a commercially available cross-linking compound.

As used herein, the terms “pharmaceutical combination”, “administeringan additional therapy”, “administering an additional therapeutic agent”and the like refer to a pharmaceutical therapy resulting from the mixingor combining of more than one active ingredient and includes both fixedand non-fixed combinations of the active ingredients. The term “fixedcombination” means that at least one of the compounds described herein,and at least one co-agent, are both administered to a patientsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that at least one of the compoundsdescribed herein, and at least one co-agent, are administered to apatient as separate entities either simultaneously, concurrently orsequentially with variable intervening time limits, wherein suchadministration provides effective levels of the two or more compounds inthe body of the patient. These also apply to cocktail therapies, e.g.the administration of three or more active ingredients.

As used herein, the terms “co-administration”, “administered incombination with” and their grammatical equivalents or the like aremeant to encompass administration of the selected therapeutic agents toa single patient, and are intended to include treatment regimens inwhich the agents are administered by the same or different route ofadministration or at the same or different times. In some embodimentsthe compounds described herein will be co-administered with otheragents. These terms encompass administration of two or more agents to ananimal so that both agents and/or their metabolites are present in theanimal at the same time. They include simultaneous administration inseparate compositions, administration at different times in separatecompositions, and/or administration in a composition in which bothagents are present. Thus, in some embodiments, the compounds describedherein and the other agent(s) are administered in a single composition.In some embodiments, the compounds described herein and the otheragent(s) are admixed in the composition.

The terms “effective amount”, “therapeutically effective amount” or“pharmaceutically effective amount” as used herein, refer to asufficient amount of at least one agent or compound being administeredwhich will relieve to some extent one or more of the symptoms of thedisease or condition being treated. The result can be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in a disease. An appropriate “effective” amount inany individual case may be determined using techniques, such as a doseescalation study.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein, e.g., as discussed in Goodman and Gilman, ThePharmacological Basis of Therapeutics, current ed.; Pergamon; andRemington's, Pharmaceutical Sciences (current edition), Mack PublishingCo., Easton, Pa. In preferred embodiments, the compounds andcompositions described herein are administered orally.

The term “acceptable” as used herein, with respect to a formulation,composition or ingredient, means having no persistent detrimental effecton the general health of the subject being treated.

The term “pharmaceutically acceptable” as used herein, refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compounds described herein, andis relatively nontoxic, i.e., the material may be administered to anindividual without causing undesirable biological effects or interactingin a deleterious manner with any of the components of the composition inwhich it is contained.

The term “carrier” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The term “pharmaceutically acceptable derivative or prodrug” as usedherein, refers to any pharmaceutically acceptable salt, ester, salt ofan ester or other derivative of a compound of Formula I, which, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound described herein or a pharmaceutically activemetabolite or residue thereof. Particularly favored derivatives orprodrugs are those that increase the bioavailability of the compoundsdescribed herein when such compounds are administered to a patient(e.g., by allowing orally administered compound to be more readilyabsorbed into blood) or which enhance delivery of the parent compound toa biological compartment (e.g., the brain or lymphatic system).

The term “pharmaceutically acceptable salt” as used herein, refers tosalts that retain the biological effectiveness of the free acids andbases of the specified compound and that are not biologically orotherwise undesirable. Compounds described herein may possess acidic orbasic groups and therefore may react with any of a number of inorganicor organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. These salts can be prepared in situduring the final isolation and purification of the compounds describedherein, or by separately reacting a purified compound in its free baseform with a suitable organic or inorganic acid, and isolating the saltthus formed. Examples of pharmaceutically acceptable salts include thosesalts prepared by reaction of the compounds described herein with amineral or organic acid or an inorganic base, such salts including,acetate, acrylate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, bisulfite, bromide, butyrate,butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate,chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate,digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate,hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate,maleate, malonate, methanesulfonate, mandelate. metaphosphate,methanesulfonate, methoxybenzoate, methylbenzoate,monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate,nicotinate, nitrate, palmoate, pectinate, persulfate,3-phenylpropionate, phosphate, picrate, pivalate, propionate,pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate,phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate,sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylate undeconate and xylenesulfonate. Other acids, suchas oxalic, while not in themselves pharmaceutically acceptable, may beemployed in the preparation of salts useful as intermediates inobtaining the compounds described herein and their pharmaceuticallyacceptable acid addition salts. (See for example Berge et al., J. Pharm.Sci. 1977, 66, 1-19.) Further, those compounds described herein whichmay comprise a free acid group may react with a suitable base, such asthe hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation, with ammonia, or with a pharmaceutically acceptableorganic primary, secondary or tertiary amine. Representative alkali oralkaline earth salts include the lithium, sodium, potassium, calcium,magnesium, and aluminum salts and the like. Illustrative examples ofbases include sodium hydroxide, potassium hydroxide, choline hydroxide,sodium carbonate, N⁺(C₁₋₄ alkyl)₄OH⁻, and the like. Representativeorganic amines useful for the formation of base addition salts includeethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine,piperazine and the like. It should be understood that the compoundsdescribed herein also include the quaternization of any basicnitrogen-containing groups they may contain. Water or oil-soluble ordispersible products may be obtained by such quaternization. See, forexample, Berge et al., supra.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “metabolite,” as used herein, refers to a derivative of acompound which is formed when the compound is metabolized.

The term “active metabolite,” as used herein, refers to a biologicallyactive derivative of a compound that is formed when the compound ismetabolized.

The term “metabolized,” as used herein, refers to the sum of theprocesses (including, but not limited to, hydrolysis reactions andreactions catalyzed by enzymes) by which a particular substance ischanged by an organism. Thus, enzymes may produce specific structuralalterations to a compound. For example, cytochrome P450 catalyzes avariety of oxidative and reductive reactions while uridine diphosphateglucuronyltransferases catalyze the transfer of an activatedglucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,carboxylic acids, amines and free sulphydryl groups. Further informationon metabolism may be obtained from The Pharmacological Basis ofTherapeutics, 9th Edition, McGraw-Hill (1996).

Compounds

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments described herein may beemployed in practicing the invention. It is intended that the followingclaims define the scope of the invention and that methods and structureswithin the scope of these claims and their equivalents be coveredthereby.

Described herein are compounds of Formula I:

wherein:

-   -   n is 0, 1, or 2;    -   R₁ and R₂ are independently selected from H, (C₁-C₆)alkyl,        (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₁-C₆)heteroalkyl,        (C₁-C₆)heteroalkenyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl,        (C₃-C₈)heterocycloalkyl, (C₃-C₈)heterocycloalkenyl, aryl, and        heteroaryl, any of which is optionally substituted with 1 or 2        independently selected R_(x) groups;    -   or R₁ and R₂ together with the nitrogen atom to which they are        attached form a 4-to 8-membered heterocycloalkyl or        heterocycloalkenyl group, any of which is optionally substituted        with 1 or 2 independently selected R_(x) groups;    -   Ar is selected from phenyl, naphthyl, and a monocylic or        bicyclic heteroaryl group, any of which is optionally        substituted with 1 or 2 independently selected R_(x) groups, or        with a phenyl, O-phenyl, or OCH₂-phenyl in which the phenyl        group is further optionally substituted with 1 or 2        independently selected R_(x) groups;    -   R₃ is L₁-L₂-R₄, where L₁ is selected from a bond, O, NR₁, and S;        L₂ is selected from a bond, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,        (C₁-C₆)alkynyl, (C₁-C₆)heteroalkyl, (C₁-C₆)heteroalkenyl,        (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, (C₃-C₈)heterocycloalkyl,        and (C₃-C₈)heterocycloalkenyl;        -   and R₄ is selected from H, cycloalkyl, cycloalkenyl,            heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl,            any of which is optionally substituted with 1 or 2            independently selected R_(x) groups    -   R_(x) is be L_(s1)L_(s2)R_(s), wherein each L_(s1) and L_(s2) is        independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—,        —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,        —OC(O)NH—, —NHC(O)O—, (C₁-C₆) alkyl, and —(C₂-C₆) alkenyl; and        R_(s) is selected from hydrogen, alkyl, cycloalkyl, aryl,        heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto,        alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,        alkylsulfone, arylsulfone, cyano, halo, isocyanato, thiocyanato,        isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, silyl, and        amino, including mono- and di-substituted amino groups, and the        protected derivatives thereof;

or a pharmaceutically acceptable salt, prodrug, solvate, polymorph,tautomer, or isomer thereof.

In some embodiments, n is 0; in other embodiments, n is 1. In furtherembodiments, R₁ and R₂ together with the nitrogen atom to which they areattached form a 4-to 8-membered heterocycloalkyl or heterocycloalkenylgroup, any of which is optionally substituted with 1 or 2 independentlyselected R_(x) groups. In still further embodiments, R₁ and R₂ togetherwith the nitrogen atom to which they are attached form a 4-to 8-memberedheterocycloalkyl. In yet further embodiments, the heterocycloalkyl groupis a 5-membered heterocycloalkyl. In alternative embodiments, theheterocycloalkyl group is a 6-membered heterocycloalkyl. In furtherembodiments, the heterocycloalkyl group contains a single N atom,whereas in alternative embodiments, the heterocycloalkyl group containstwo N atoms. In further embodiments, the heterocycloalkyl group, isunsubstituted. In alternative embodiments, the heterocycloalkyl group issubstituted with one R_(x) group. In still further embodiments, R_(x) isL_(s1)L_(s2)R_(s), wherein each L_(s1 and L) _(s2) is independentlyselected from a bond, —O—, —C(═O)—, —NH—, —NHC(O)—, —C(O)NH—, —OC(O)NH—,—NHC(O)O—, (C₁-C₆) alkyl, and —(C₂-C₆) alkenyl. In a further embodiment,R_(s) is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,heteroalicyclic, hydroxy, alkoxy, aryloxy, carbonyl, perhaloalkyl,perfluoroalkyl, and amino, including mono- and di-substituted aminogroups.

In further or alternative embodiments of any of the aforementionedembodiments, Ar is selected from a phenyl, pyridyl, or pyrimidyl group.In further embodiments, Ar is a phenyl group. In further embodiments, Aris substituted with a phenyl, O-phenyl, or OCH₂-phenyl in which thephenyl group is further optionally substituted with 1 or 2 independentlyselected R_(x) groups. In still further embodiments, R_(x) isL_(s1)L_(s2)R_(s), wherein each L_(s1) and L_(s2) is independentlyselected from a bond, —O—, —C(═O)—, —NH—, —NHC(O)—, —C(O)NH—, —OC(O)NH—,—NHC(O)O—, (C₁-C₆) alkyl, and —(C₂-C₆) alkenyl. In a further embodiment,R_(s) is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,heteroalicyclic, hydroxy, alkoxy, aryloxy, carbonyl, perhaloalkyl,perfluoroalkyl, and amino, including mono- and di-substituted aminogroups. In an alternative embodiment, Ar is substituted with one or twoR_(x) groups. In still further embodiments, R_(x) is L_(s1)L_(s2)R_(s),wherein each L_(s1) and L_(s2) is independently selected from a bond,—O—, —C(═O)—, —NH—, —NHC(O)—, —C(O)NH—, —OC(O)NH—, —NHC(O)O—, (C₁-C₆)alkyl, and —(C₂-C₆) alkenyl. In a further embodiment, R_(s) is selectedfrom hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic,hydroxy, alkoxy, aryloxy, carbonyl, perhaloalkyl, perfluoroalkyl, andamino, including mono- and di-substituted amino groups.

In further or alternative embodiments of any of the aforementionedembodiments, R₃ is L₁-L₂-R₄, where L₁ is selected from a bond, O, andNR₁. In further embodiments, L₂ is selected from a bond, (C₁-C₆)alkyl,(C₁-C₆)alkenyl, (C₁-C₆)heteroalkyl, (C₃-C₈)cycloalkyl, and(C₃-C₈)heterocycloalkyl. In further embodiments, L₂ is selected from(C₁-C₆)alkyl and (C₁-C₆)alkenyl. In alternative embodiments, L₂ isselected from a bond. In alternative embodiments, L₂ is selected from(C₁-C₆)alkyl. In alternative embodiments, L₂ is selected from(C₁-C₆)alkenyl. In further embodiments, R₄ is selected from H, aryl, andheteroaryl. In further embodiments, R₄ is H. In alternative embodiments,R₄ is aryl. In alternative embodiments, R₄ is heteroaryl. In analternative embodiment, R₄ is a phenyl, substituted with one or twoR_(x) groups. In still further embodiments, R_(x) is L_(s1)L_(s2)R_(s),wherein each L_(s1) and L_(s2) is independently selected from a bond,—O—, —C(═O)—, —NH—, —NHC(O)—, —C(O)NH—, —OC(O)NH—, —NHC(O)O—, (C₁-C₆)alkyl, and —(C₂-C₆) alkenyl. In a further embodiment, R_(s) is selectedfrom hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic,hydroxy, alkoxy, aryloxy, carbonyl, perhaloalkyl, perfluoroalkyl, andamino, including mono- and di-substituted amino groups. In analternative embodiment, R₄ is an unsubstituted phenyl.

Provided herein are compounds or pharmaceutically acceptable salts ofFormula II:

wherein:

-   -   n is 0 or 1,    -   R₅ is selected from halogen, C₁-C₆ alkyl, hydroxy, —O(C₁-C₆        alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆ alkyl),        —(C₁-C₆ haloalkyl), —NHCOH, —NHCO(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)COH, —N(C₁-C₆ alkyl)CO(C₁-C₆ alkyl), —NHSO₂H, —NHSO₂(C₁-C₆        alkyl), —N(C₁-C₆ alkyl)SO₂H, —N(C₁-C₆ alkyl) SO₂(C₁-C₆ alkyl),        —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, and SO₂(C₁-C₆        alkyl),

or a pharmaceutically acceptable salt, prodrug, solvate, polymorph,tautomer, or isomer thereof.

Provided herein are compounds or pharmaceutically acceptable salts ofFormula III:

wherein:

-   -   n is 0 or 1;    -   R₅ is selected from hydrogen, halogen, C₁-C₆ alkyl, hydroxy,        —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆        alkyl), —(C₁-C₆ haloalkyl), —NHCOH, —NHCO(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)COH, —N(C₁-C₆ alkyl)CO(C₁-C₆ alkyl), —NHSO₂H, —NHSO₂(C₁-C₆        alkyl), —N(C₁-C₆ alkyl)SO₂H, —N(C₁-C₆ alkyl) SO₂(C₁-C₆ alkyl),        —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆ alkyl)₂, and SO₂(C₁-C₆        alkyl); and    -   R₆ is selected from hydrogen, halogen and a C₁-C₆ alkyl, phenyl,        —O-phenyl, or —O-benzyl group optionally substituted with        halogen, C₁-C₆ alkyl, hydroxy, —O(C₁-C₆ alkyl), —CO₂H, or        —CO₂(C₁-C₆ alkyl),

or a pharmaceutically acceptable salt, prodrug, solvate, polymorph,tautomer, or isomer thereof.

Provided herein are compounds or pharmaceutically acceptable salts ofFormula IV or Formula V:

wherein:

-   -   R₇ is hydrogen, halogen, or C₁-C₆ alkyl; and    -   R₈ is a phenyl group optionally substituted with one or two        groups independently selected from halogen, C₁-C₆ alkyl,        hydroxy, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —NHCOH, —NHCO(C₁-C₆        alkyl), —N(C₁-C₆ alkyl)COH, —N(C₁-C₆ alkyl)CO(C₁-C₆ alkyl),        —NHSO₂H, —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂H, —N(C₁-C₆        alkyl) SO₂(C₁-C₆ alkyl), —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆        alkyl)₂, and SO₂(C₁-C₆ alkyl),

or a pharmaceutically acceptable salt, prodrug, solvate, polymorph,tautomer, or isomer thereof.

Provided herein are compounds or pharmaceutically acceptable salts ofFormula VI or Formula VII:

wherein:

-   -   R₆ is selected from hydrogen, halogen and a C₁-C₆ alkyl, phenyl,        —O-phenyl, or —O-benzyl group optionally substituted with        halogen, C₁-C₆ alkyl, hydroxy, —O(C₁-C₆ alkyl), —CO₂H, or        —CO₂(C₁-C₆ alkyl);    -   R₇ is hydrogen, halogen, or C₁-C₆ alkyl; and    -   R₈ is a phenyl group optionally substituted with one or two        groups independently selected from halogen, C₁-C₆ alkyl,        hydroxy, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆        alkyl)(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —NHCOH, —NHCO(C₁-C₆        alkyl), —N(C₁-C₆ alkyl)COH, —N(C₁-C₆ alkyl)CO(C₁-C₆ alkyl),        —NHSO₂H, —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂H, —N(C₁-C₆        alkyl) SO₂(C₁-C₆ alkyl), —CONH₂, —CONH(C₁-C₆ alkyl), —CON(C₁-C₆        alkyl)₂, and SO₂(C₁-C₆ alkyl),

or a pharmaceutically acceptable salt, prodrug, solvate, polymorph,tautomer, or isomer thereof.

In some embodiments, R₁ and R₂, together with the nitrogen atom to whichthey are attached form a heterocycloalkyl group selected from:

wherein:

-   -   each NH₂ group is optionally substituted with a C₁-C₆ alkyl        group;    -   X is O, NR or SO₂, and    -   each R is independently selected from halogen, —OH, —NH₂, —SH,        —S(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, C₁-C₆        alkyl, C₁-C₆ haloalkyl, and C₁-C₆ heteroalkyl.

In some embodiments, R is independently selected from hydrogen and C₁-C₆alkyl.

In some embodiments, each NH₂ group is unsubstituted.

In some embodiments, R₁ and R₂, together with the nitrogen atom to whichthey are attached

form a heterocycloalkyl group selected from:

In some embodiments, Ar is a phenyl, pyridyl or pyrimidyl group. In someembodiments, Ar is a phenyl, pyridyl or pyrimidyl group optionallysubstituted with one or two substituents independently selected fromhalogen and a C₁-C₆ alkyl, phenyl, —O-phenyl, or —O-benzyl groupoptionally substituted with halogen, C₁-C₆ alkyl, hydroxy, —O(C₁-C₆alkyl), —CO₂H, or —CO₂(C₁-C₆ alkyl). In some embodiments, Ar is a phenylgroup optionally substituted with one or two substituents independentlyselected from halogen and a C₁-C₆ alkyl, phenyl, —O-phenyl, or —O-benzylgroup optionally substituted with halogen, C₁-C₆ alkyl, hydroxy,—O(C₁-C₆ alkyl), —CO₂H, or —CO₂(C₁-C₆ alkyl).

In some embodiments, R₂ is hydrogen, —NH₂, —OH, —SH, —N(C₁-C₃ alkyl)₂,—NH(C₁-C₃ alkyl), —NCO₂(C₁-C₃ alkyl), —NCO₂H, —NCONH₂.

In some embodiments, R₂ is hydrogen, halogen, or a group selected fromphenyl, O-phenyl, and O—CH₂-phenyl, optionally substituted with halogenC₁-C₆ alkyl, —OH, —COOH, —COO(C₁-C₆ alkyl). In some embodiments, R₂ ishydrogen.

In some embodiments, R₄ is a phenyl group optionally substituted withone or two groups independently selected from halogen, C₁-C₆ alkyl,hydroxy, —O(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)(C₁-C₆alkyl), —(C₁-C₆ haloalkyl), —NHCOH

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is:

wherein:Y is selected from the group consisting of —CH₂CO₂R^(E), —CH₂CONHR^(J)and —COZ;Z is slected from the group consisting of Ph, —C₁₋₃alkylPh and —CH═CHPh,wherein Ph is substituted with R^(C) and R^(D) which are independentlyselected from the group comprising hydrogen, halogen, C₁-C₆ alkyl,OR^(E), NR^(G)R^(H), NR^(G)COR^(W), NR^(G)SO₂R^(W), CONR^(G)R^(H) andSO₂R^(W);R^(L) is selected from the group consisting of hydrogen, halogen, Ph,OPh and OCH₂Ph, wherein Ph is optionally substituted with halogen, C₁-C₆alkyl, OR^(E) or CO₂R^(E);R^(A) and R^(B) are independently selected from hydrogen, C₁-C₆ alkyland CO₂R^(F);R^(E) is hydrogen or C₁-C₆ alkyl;R^(F) is C₁-C₆ alkyl;R^(G) and R^(H) are independently hydrogen or C₁-C₆ alkyl or maytogether form a 5- or 6-membered ring which optionally contains onefurther heteroatom selected from NR^(E), S and O;R^(W) is C₁-C₆ alkyl; andR^(J) is CH₂Ph, (CH₂)₂Ph or (CH₂)₂OPh, wherein Ph is substituted withR^(C) and R^(D).

-   -   In some embodiments, Y is CH₂CONHCH₂Ph where the Ph is        substituted with R^(C) and R^(D), wherein R^(C) and R^(D) are as        defined above.

In other embodiments, Y is —COCH═CHPh where the phenyl group issubstituted with R^(C) and

-   -   R^(D), wherein R^(C) and R^(D) are as defined above.

In some embodiments, Y is COZ and R^(L) is Ph or OPh, wherein Ph isoptionally substituted with halogen, C₁-C₆ alkyl, OR^(E) or CO₂R^(E),and wherein R^(E) and Z are as defined above.

In some embodiments, Y is —CH₂CO₂R^(E) or —CH₂CONHR^(J), and R^(L) isOPh or OCH₂Ph, wherein

Ph is optionally substituted with halogen or C₁-C₆ alkyl, and whereinR^(E) and R^(J) are as defined in claim 1.

In some embodiments, Rc and R^(D) are independently selected from thegroup comprising hydrogen, halogen and C₁-C₆ alkyl.

In some embodiments, R^(A) is hydrogen or C₁-C₆ alkyl.

In some embodiments, R^(B) is hydrogen or C₁-C₆ alkyl.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is:

whereinY′ is selected from the group comprising OR^(C1) and NHR^(D1);R^(L1) is selected from the group consisting of hydrogen, halogen, Ph,OPh and OCH₂Ph, wherein Ph is optionally substituted with halogen, C₁-C₆alkyl, OR^(C1) or CO₂R^(C1);R^(A1) and R^(B1) are independently selected from hydrogen, C₁-C₆ alkyland CO₂R^(W1);R^(C1) is hydrogen or C₁-C₆ alkyl;R^(D1) is CH₂Ph, (CH₂)₂Ph or (CH₂)₂OPh, wherein Ph is substituted withR^(E1) and R^(F1);R^(E1) and R^(F1) are independently selected from the group comprisinghydrogen, halogen, C₁-C₆ alkyl, OR^(C1), NR^(G1)R^(H1), NR^(G1)COR^(W1),NR^(G1)SO₂R^(W1), CONR^(G1)R^(H1) or SO₂R^(W1);R^(G1) and R^(H1) are independently hydrogen or C₁-C₆ alkyl or maytogether form a 5- or 6-membered ring which optionally contains onefurther heteroatom selected from NR^(C1), S and O; andR^(W1) is C₁-C₆ alkyl.

In some embodiments, Y′ is NHCH₂Ph where the Ph is substituted withR^(E1) and R^(F1), wherein R^(E1) and R^(F1) are as defined above.

In some embodiments, R^(E1) and R^(F1) are independently selected fromthe group comprising hydrogen, halogen and C₁-C₆ alkyl.

In some embodiments, R^(A1) is hydrogen or C₁-C₆ alkyl.

In some embodiments, R^(B1) is hydrogen or C₁-C₆ alkyl.

In some embodiments, R^(L1) is OPh or OCH₂Ph, wherein Ph isunsubstituted or is substituted with halogen or C₁-C₆ alkyl.

According to a further embodiment described herein, Y′ is CH₂CONHCH₂Phwhere the phenyl group is substituted with R^(C1) and R^(D1) as definedabove, including in the meta or para position. Suitably, R^(C1) andR^(D1) are independently selected from the group comprising hydrogen,halogen and C₁-C₆ alkyl. Particular values of R^(C1) and R^(D1) includehydrogen, fluoro, chloro and trifluoromethyl. In one embodiment R^(A1)and R^(B1) are both hydrogen. In one embodiment R^(L1) is OPh or OCH₂Ph,including in the meta or para position, wherein Ph is optionallysubstituted with halogen or C₁-C₆ alkyl but is preferably unsubstituted.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is:

wherein

-   Y″ is selected from the group comprising Ph, —C₁₋₃alkylPh and    —CH═CHPh, wherein Ph is substituted with R^(C2) and R^(D2) which are    independently selected from the group comprising hydrogen, halogen,    C₁-C₆ alkyl, OR^(E2), NR^(G2)R^(H2), NR^(G2) COR^(W2), NR^(G2)    SO₂R^(W2), CONR^(G2)R^(H2) and SO₂R^(W2);-   R^(L2) is selected from the group consisting of hydrogen, halogen,    Ph, OPh and OCH₂Ph, wherein Ph is optionally substituted with    halogen, C₁-C₆ alkyl, OR^(E2) or CO₂R^(E2);-   R^(A2) and R^(B2) are independently selected from hydrogen, C₁-C₆    alkyl and CO₂R^(F2);-   R^(E2) is hydrogen or C₁-C₆ alkyl;-   R^(F2) is C₁-C₆ alkyl;-   R^(G2) and R^(H2) are independently hydrogen or C₁-C₆ alkyl or may    together form a 5- or 6-membered ring which optionally contains one    further heteroatom selected from NR^(E2), S and O; and-   R^(W2) is C₁-C₆ alkyl.

In some embodiments, Y″ is —CH═CHPh where the phenyl group issubstituted with R^(C2) and R^(D2), wherein R^(C2) and R^(D2) are asdefined above.

In some embodiments, R^(C2) and R^(D2) are independently selected fromthe group comprising hydrogen, halogen and C₁-C₆ alkyl.

In some embodiments, R^(A2) is hydrogen or C₁-C₆ alkyl.

In some embodiments, R^(B2) is hydrogen or C₁-C₆ alkyl.

In some embodiments, R^(L2) is Ph or OPh, wherein Ph is optionallysubstituted with halogen, C₁-C₆ alkyl, OR^(E2) or CO₂R^(E2).

According to one embodiment described herein, Y″ is —COCH═CHPh where thephenyl group is substituted with R^(C2) and R^(D2) as defined above,including in the meta or para position. Suitably, R^(C2) and R^(D2) areindependently selected from the group comprising hydrogen, halogen andC₁-C₆ alkyl. Typically, R^(C2) and R^(D2) are both hydrogen. In oneembodiment R^(A2) and R^(B2) are both hydrogen. Preferably R^(L2) is Phor OPh, including in the meta or para position, wherein Ph is optionallysubstituted with halogen, C₁-C₆ alkyl, OR^(E2) or CO₂R^(E2), especiallyOR^(E2) or CO₂R^(E2).

Compounds described herein that have been shown to work well areOGT4325, OGT4355, OGT4344, OGT4420, OGT4421, OGT4165, OGT4154, OGT4155and OGT3935.

-   (E)-N-[2-((S)-3-Amino-pyrrolidin-1-yl)-2-oxo-ethyl]-3-phenyl-N-(3′-trifluoromethoxy-biphenyl-4-yl)-acrylamide    (OGT4325)-   4′-{[2-((S)-3-Amino-pyrrolidin-1-yl)-2-oxo-ethyl]-[(E)-(3-phenylacryloyl)]-amino}-biphenyl-3-carboxylic    acid, ethyl ester (OGT4355)-   (E)-N-[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-N-(4-phenoxyphenyl)-3-phenylacrylamide    (OGT4344)-   (E)-N-[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-N-[4-(4-trifluoromethoxy-benzyloxy)phenyl]-3-phenylacrylamide    (OGT4420)-   (E)-N-[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-N-[4-(3,4-dichloro-benzyloxy)phenyl]-3-phenylacrylamide    (OGT4421)-   2-[[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxyphenyl)amino]-N-[3,5-bis-(trifluoromethyl)benzyl]acetamide    (OGT4165)-   2-[[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-(4-phenoxyphenyl)amino]-N-(3-chlorobenzyl)acetamide    (OGT4154)-   2-[[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-(4-phenoxyphenyl)amino]-N-[3-fluoro-5-(trifluoromethyl)benzyl]acetamide    (OGT4155)-   2-[[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-(2-phenoxyphenyl)amino]-N-(3-chlorobenzyl)acetamide    (OGT3935)

Synthetic Procedures

In another aspect, methods for synthesizing the compounds of Formula I(including without limitation any of the compounds specifically orgenerically described herein) are provided. In some embodiments, thecompounds described herein can be prepared by the methods describedbelow. The procedures and examples below are intended to illustratethose methods. Neither the procedures nor the examples should beconstrued as limiting the invention in any way. Compounds describedherein may also be synthesized using standard synthetic techniques knownto those of skill in the art or using methods known in the art incombination with methods described herein. In additions, solvents,temperatures and other reaction conditions presented herein may varyaccording to the practice and knowledge of those of skill in the art.

The starting materials used for the synthesis of the compounds ofFormula I (including without limitation any of the compoundsspecifically or generically described herein) can be obtained fromcommercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis.),Sigma Chemical Co. (St. Louis, Mo.), or the starting materials can besynthesized. The compounds described herein, and other related compoundshaving different substituents can be synthesized using techniques andmaterials known to those of skill in the art, such as described, forexample, in March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992);Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B(Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANICSYNTHESIS 3^(rd) Ed., (Wiley 1999) (all of which are incorporated byreference in their entirety). General methods for the preparation ofcompound as disclosed herein may be derived from known reactions in thefield, and the reactions may be modified by the use of appropriatereagents and conditions, as would be recognized by the skilled person,for the introduction of the various moieties found in the formulae asprovided herein. As a guide the following synthetic methods may beutilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein can be modified using variouselectrophiles or nucleophiles to form new functional groups orsubstituents. The table below entitled “Examples of Covalent Linkagesand Precursors Thereof” lists selected examples of covalent linkages andprecursor functional groups which yield and can be used as guidancetoward the variety of electrophiles and nucleophiles combinationsavailable. Precursor functional groups are shown as electrophilic groupsand nucleophilic groups.

Examples of Covalent Linkages and Precursors Thereof

Covalent Linkage Product Electrophile Nucleophile Carboxamides Activatedesters Amines/anilines Carboxamides Acyl azides Amines/anilinesCarboxamides Acyl halides Amines/anilines Esters Acyl halidesAlcohols/phenols Esters Acyl nitriles Alcohols/phenols Carboxamides Acylnitriles Amines/anilines Imines Aldehydes Amines/anilines HydrazonesAldehydes or ketones Hydrazines Oximes Aldehydes or ketonesHydroxylamines Alkyl amines Alkyl halides Amines/anilines Esters Alkylhalides Carboxylic acids Thioethers Alkyl halides Thiols Ethers Alkylhalides Alcohols/phenols Thioethers Alkyl sulfonates Thiols Esters Alkylsulfonates Carboxylic acids Ethers Alkyl sulfonates Alcohols/phenolsEsters Anhydrides Alcohols/phenols Carboxamides AnhydridesAmines/anilines Thiophenols Aryl halides Thiols Aryl amines Aryl halidesAmines Thioethers Aziridines Thiols Boronate esters Boronates GlycolsCarboxamides Carboxylic acids Amines/anilines Esters Carboxylic acidsAlcohols Hydrazines Hydrazides Carboxylic acids N-acylureas orAnhydrides Carbodiimides Carboxylic acids Esters Diazoalkanes Carboxylicacids Thioethers Epoxides Thiols Thioethers Haloacetamides ThiolsAmmotriazines Halotriazines Amines/anilines Triazinyl ethersHalotriazines Alcohols/phenols Amidines Imido esters Amines/anilinesUreas Isocyanates Amines/anilines Urethanes Isocyanates Alcohols/phenolsThioureas Isothiocyanates Amines/anilines Thioethers Maleimides ThiolsPhosphite esters Phosphoramidites Alcohols Silyl ethers Silyl halidesAlcohols Alkyl amines Sulfonate esters Amines/anilines ThioethersSulfonate esters Thiols Esters Sulfonate esters Carboxylic acids EthersSulfonate esters Alcohols Sulfonamides Sulfonyl halides Amines/anilinesSulfonate esters Sulfonyl halides Phenols/alcohols

Use of Protecting Groups

During the synthesis of the compounds of Formula I, labile functionalgroups in the intermediate compounds may be protected. For example, itmay be necessary to protect reactive functional groups, for examplehydroxy, amino, imino, thio or carboxy groups, where these are desiredin the final product, to avoid their unwanted participation in thereactions. The protecting groups may be removed at any stage in thesynthesis of the compounds of Formula I or may be present on the finalcompound of Formula I. A comprehensive discussion of the ways in whichvarious labile functional groups may be protected and methods forcleaving the resulting protected derivatives is given in for exampleProtective Groups in Organic Chemistry, T. W. Greene and P. G. M. Wuts(Wiley-Interscience, New York, 2^(nd) edition, 1991).

Protecting groups are used to block some or all reactive moieties andprevent such groups from participating in chemical reactions until theprotective group is removed. Protected derivatives are useful in thepreparation of the compounds described herein or in themselves may beactive as inhibitors. It is preferred that each protective group beremovable by a different means. Protective groups that are cleaved undertotally disparate reaction conditions fulfill the requirement ofdifferential removal. Protective groups can be removed by acid, base,and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and may be used to protect carboxyand hydroxy reactive moieties in the presence of amino groups protectedwith Cbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties maybe blocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl in the presence of amines blocked with acid labilegroups such as t-butyl carbamate or with carbamates that are both acidand base stable but hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, or they may be blocked with oxidatively-removable protectivegroups such as 2,4-dimethoxybenzyl, while co-existing amino groups maybe blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Protecting or blocking groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference in their entirety.

Further Forms of the Compounds Isomers

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) may exist in the form of opticalisomers, e.g. diastereoisomers and mixtures of isomers in all ratios,e.g. racemic mixtures. This includes in particular the isomeric forms (Ror S). The different isomeric forms may be separated or resolved onefrom the other by conventional methods, or any given isomer may beobtained by conventional synthetic methods or by stereospecific orasymmetric synthesis. Where a compound contains an alkene moiety, thealkene can be presented as a cis or trans isomer or a mixture thereof.When an isomeric form of a compound described herein is providedsubstantially free of other isomers, it will preferably contain lessthan 5% w/w, more preferably less than 2% w/w and especially less than1% w/w of the other isomers.

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) may exist as geometric isomers. Thecompounds described herein may possess one or more double bonds. Thecompounds presented herein include all cis, trans, syn, anti, entgegen(E), and zusammen (Z) isomers as well as the corresponding mixturesthereof. In some situations, compounds may exist as tautomers. Thecompounds described herein include all possible tautomers within theformulas described herein.

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) may possess one or more chiralcenters and each center may exist in the R or S configuration. Thecompounds described herein include all diastereomeric, enantiomeric, andepimeric forms as well as the corresponding mixtures thereof. Inadditional embodiments of the compounds and methods provided herein,mixtures of enantiomers and/or diastereoisomers, resulting from a singlepreparative step, combination, or interconversion may also be useful forthe applications described herein.

In some embodiments, the compounds of Formula I (including withoutlimitation any of the compounds specifically or generically describedherein, including the compounds presented in the tables) can be preparedas their individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomers. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of the compoundsdescribed herein, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chiralchromatography, or preferably, by separation/resolution techniques basedupon differences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions,” John WileyAnd Sons, Inc., 1981, herein incorporated by reference in its entirety.

Labeled Compounds

It should be understood that the compounds of Formula I (includingwithout limitation any of the compounds specifically or genericallydescribed herein, including the compounds presented in the tables)include their isotopically-labeled equivalents, including their use fortreating disorders. For example, provided herein are methods of treatingdiseases, by administering isotopically-labeled compounds of Formula I.The isotopically-labeled compounds described herein can be administeredas pharmaceutical compositions. Thus, the compounds described hereinalso include their isotopically-labeled isomers, which are identical tothose recited herein, but for the fact that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds described hereininclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine and chloride, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds describedherein, pharmaceutically acceptable salts, esters, prodrugs, solvate,hydrates or derivatives thereof which contain the aforementionedisotopes and/or other isotopes of other atoms are included herein.Certain isotopically-labeled compounds, for example those into whichradioactive isotopes such as ³H and ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i.e., ³Hand carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically labeledcompounds, pharmaceutically acceptable salts, esters, prodrugs,solvates, hydrates or derivatives thereof can generally be prepared bycarrying out procedures described herein, by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

The compounds described herein may be labeled by other means, including,but not limited to, the use of chromophores or fluorescent moieties,bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) may also exist as theirpharmaceutically acceptable salts, which may also be useful for treatingdisorders. For example, described are methods of treating diseases, byadministering pharmaceutically acceptable salts of the compoundsdescribed herein. The pharmaceutically acceptable salts can beadministered as pharmaceutical compositions.

Thus, the compounds of Formula I (including without limitation any ofthe compounds specifically or generically described herein, includingthe compounds presented in the tables) can be prepared aspharmaceutically acceptable salts formed when an acidic proton presentin the parent compound either is replaced by a metal ion, for example analkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base. Base addition salts can also beprepared by reacting the free acid form of the compounds describedherein with a pharmaceutically acceptable inorganic or organic base,including, but not limited to organic bases such as ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine, andthe like and inorganic bases such as aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. In addition, the salt forms of the disclosed compounds can beprepared using salts of the starting materials or intermediates.

Further, the compounds of Formula I (including without limitation any ofthe compounds specifically or generically described herein, includingthe compounds presented in the tables) can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, and muconic acid.

The compounds described herein may be provided as a salt, preferably asa pharmaceutically acceptable salt of compounds of Formula I. Examplesof pharmaceutically acceptable salts of these compounds include thosederived from organic acids such as acetic acid, malic acid, tartaricacid, citric acid, lactic acid, oxalic acid, succinic acid, fumaricacid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid,mandelic acid, methanesulphonic acid, benzenesulphonic acid andp-toluenesulphonic acid, mineral acids such as hydrochloric andsulphuric acid and the like, giving methanesulphonate,benzenesulphonate, p-toluenesulphonate, hydrochloride and sulphate, andthe like, respectively or those derived from bases such as organic andinorganic bases. Examples of suitable inorganic bases for the formationof salts of compounds described herein include the hydroxides,carbonates, and bicarbonates of ammonia, lithium, sodium, calcium,potassium, aluminium, iron, magnesium, zinc and the like. Salts can alsobe formed with suitable organic bases. Such bases suitable for theformation of pharmaceutically acceptable base addition salts withcompounds described herein include organic bases, which are nontoxic andstrong enough to form salts. Such organic bases are already well knownin the art and may include amino acids such as arginine and lysine,mono-, di-, or trihydroxyalkylamines such as mono-, di-, andtriethanolamine, choline, mono-, di-, and trialkylamines, such asmethylamine, dimethylamine, and trimethylamine, guanidine;N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine;N-benzylphenethylamine; tris(hydroxymethyl)aminomethane; and the like.

Salts may be prepared in a conventional manner using methods well knownin the art. Acid addition salts of said basic compounds may be preparedby dissolving the free base compounds according to the first aspectdescribed herein in aqueous or aqueous alcohol solution or othersuitable solvents containing the required acid. Where a compounddescribed herein contains an acidic function, a base salt of saidcompound may be prepared by reacting said compound with a suitable base.The acid or base salt may separate directly or can be obtained byconcentrating the solution e.g. by evaporation.

Solvates

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) may also exist in various solvatedforms, which may also be useful for treating disorders. For example,described are methods of treating diseases, by administering solvates ofthe compounds described herein. The solvates can be administered aspharmaceutical compositions. Preferably the solvates arepharmaceutically acceptable solvates.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and may be formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol. Solvates of the compounds describedherein can be conveniently prepared or formed during the processesdescribed herein. By way of example only, hydrates of the compoundsdescribed herein can be conveniently prepared by recrystallization froman aqueous/organic solvent mixture, using organic solvents including,but not limited to, dioxane, tetrahydrofuran or methanol. In addition,the compounds provided herein can exist in unsolvated as well assolvated forms. In general, the solvated forms are considered equivalentto the unsolvated forms for the purposes of the compounds and methodsprovided herein.

Polymorphs

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) may also exist in various polymorphicstates, all of which are herein contemplated, and which may also beuseful for treating disorders. For example, described are methods oftreating diseases, by administering polymorphs of the compoundsdescribed herein. The various polymorphs can be administered aspharmaceutical compositions.

Thus, the compounds of Formula I (including without limitation any ofthe compounds specifically or generically described herein, includingthe compounds presented in the tables) include all their crystallineforms, known as polymorphs. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound.Polymorphs may have different X-ray diffraction patterns, infraredspectra, melting points, density, hardness, crystal shape, optical andelectrical properties, stability, solvates and solubility. Variousfactors such as the recrystallization solvent, rate of crystallization,and storage temperature may cause a single crystal form to dominate.

Prodrugs

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) may also exist in prodrug form, whichmay also be useful for treating disorders. For example, described aremethods of treating diseases, by administering prodrugs of the compoundsdescribed herein. The prodrugs can be administered as pharmaceuticalcompositions.

Prodrugs are generally drug precursors that, following administration toa subject and subsequent absorption, are converted to an active, or amore active species via some process, such as conversion by a metabolicpathway. Some prodrugs have a chemical group present on the prodrug thatrenders it less active and/or confers solubility or some other propertyto the drug. Once the chemical group has been cleaved and/or modifiedfrom the prodrug the active drug is generated. Prodrugs are often usefulbecause, in some situations, they may be easier to administer than theparent drug. They may, for instance, be bioavailable by oraladministration whereas the parent is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.An example, without limitation, of a prodrug would be a compound asdescribed herein which is administered as an ester (the “prodrug”) tofacilitate transmittal across a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. A further example of a prodrug might bea short peptide (polyamino acid) bonded to an acid group where thepeptide is metabolized to reveal the active moiety.

Prodrugs may be designed as reversible drug derivatives, for use asmodifiers to enhance drug transport to site-specific tissues. The designof prodrugs to date has been to increase the effective water solubilityof the therapeutic compound for targeting to regions where water is theprincipal solvent. See, e.g., Fedorak et al., Am. J. Physiol.,269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994);Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H.Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int.J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci.,64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, all incorporated herein in theirentirety.

Pharmaceutically acceptable prodrugs of the compounds of Formula I(including without limitation any of the compounds specifically orgenerically described herein, including the compounds presented in thetables) include, but are not limited to, esters, carbonates,thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,quaternary derivatives of tertiary amines, N-Mannich bases, Schiffbases, amino acid conjugates, phosphate esters, metal salts andsulfonate esters. Various forms of prodrugs are well known in the art.See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p. 309-396; Bundgaard, H. “Design and Application of Prodrugs” in ATextbook of Drug Design and Development, Krosgaard-Larsen and H.Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., AdvancedDrug Delivery Review, 1992, 8, 1-38, each of which is incorporatedherein by reference. The prodrugs described herein include, but are notlimited to, the following groups and combinations of these groups; aminederived prodrugs:

Hydroxy prodrugs include, but are not limited to acyloxyalkyl esters,alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters and disulfidecontaining esters.

In some embodiments, prodrugs include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxy or carboxylic acid group of compounds ofthe present invention. The amino acid residues include but are notlimited to the naturally occurring amino acids commonly designated bythree letter symbols and also includes 4-hydroxyproline, hydroxylysine,demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithineand methionine sulfone. Additional types of prodrugs are alsoencompassed.

Prodrug derivatives of compounds described herein can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). By way of example only, appropriate prodrugscan be prepared by reacting a non-derivatized compound of Formula I witha suitable carbamylating agent, such as, but not limited to,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike. Prodrug forms of the herein described compounds, wherein theprodrug is metabolized in vivo to produce a derivative as set forthherein are included within the scope of the claims. Indeed, some of theherein-described compounds may be a prodrug for another derivative oractive compound.

Compounds of Formula I having free amino, amido, hydroxy or carboxylicgroups can be converted into prodrugs. For instance, free carboxylgroups can be derivatized as amides or alkyl esters. Free hydroxy groupsmay be derivatized using groups including but not limited tohemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups.

Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers wherein the acyl group may be an alkyl ester, optionallysubstituted with groups including but not limited to ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem. 1996, 39, 10. Free amines can alsobe derivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including but not limited toether, amine and carboxylic acid functionalities. Phosphate esterfunctionalities may also be used as prodrug moieties.

Sites on the aromatic ring portions of compounds of the compoundsdescribed herein may be susceptible to various metabolic reactions,therefore incorporation of appropriate substituents on the aromatic ringstructures, can reduce, minimize or eliminate this metabolic pathway.

Compound Purity

Because the compounds described herein are intended for use inpharmaceutical compositions, it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5%, e.g. 10 to 59% of a compound of the Formula I.

Pharmaceutical Compositions

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) may be administered in the form of apharmaceutical composition in accordance with one aspect describedherein. Such compositions may be presented in conventional dosage formsprepared by combining a compound of Formula I (“active ingredient”) withstandard pharmaceutical carriers or excipients according to conventionalprocedures well known in the art. The procedures may involve mixing,granulating and compressing or dissolving the ingredients as appropriateto the desired preparation.

The active ingredient or pharmaceutical composition can be administeredsimultaneously, separately or sequentially with another appropriatetreatment for the fungal disease being treated.

The present invention can be administered alone or as a pharmaceuticalcomposition, thus the invention further provides pharmaceuticalcompositions and methods of making said pharmaceutical composition. Insome embodiments, the pharmaceutical compositions comprise an effectiveamount of the compounds of Formula I, or a pharmaceutically acceptablesalt, prodrug, solvate, polymorph, tautomer or isomer thereof. Thepharmaceutical composition may comprise of admixing at least one activeingredient, or a pharmaceutically acceptable salt, prodrug, solvate,polymorph, tautomer or isomer thereof, together with one or morecarriers, excipients, buffers, adjuvants, stabilizers, or othermaterials well known to those skilled in the art and optionally othertherapeutic agents. The formulations may conveniently be presented inunit dosage form and may be prepared by any methods well known in theart of pharmacy.

Examples of excipients that may be used in conjunction with the presentinvention include, but are not limited to water, saline, dextrose,glycerol or ethanol. The injectable compositions may also optionallycomprise minor amounts of non-toxic auxiliary substances such as wettingor emulsifying agents, pH buffering agents, stabilizers, solubilityenhancers, and other such agents, such as for example, sodium acetate,sorbitan monolaurate, triethanolamine oleate and cyclodextrins.

Example of pharmaceutically acceptable carriers that may optionally beused include, but are not limited to aqueous vehicles, nonaqueousvehicles, antimicrobial agents, isotonic agents, buffers, antioxidants,local anesthetics, suspending and dispersing agents, emulsifying agents,sequestering or chelating agents and other pharmaceutically acceptablesubstances.

The active ingredient or pharmaceutical composition may be administeredto a subject by any of the routes conventionally used for drugadministration, for example they may be adapted for oral (includingbuccal, sublingual), topical (including transdermal), nasal (includinginhalation), rectal, vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) administration to mammalsincluding humans. The most suitable route for administration in anygiven case will depend upon the particular compound or pharmaceuticalcomposition, the subject, and the nature and composition and severity ofthe disease and the physical condition of the subject. Such compositionsmay be prepared by any method known in the art of pharmacy, for exampleby bringing into association the active ingredient with the carrier(s)or excipient(s).

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; filler, for example lactose, sugar,maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions syrups or elixirs, or may be presentedas a dry product for reconstitution with water or other suitable vehiclebefore use. Such liquid preparations may contain conventional additives,such as suspending agents, for example sorbitol, methyl cellulose,glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose,aluminium stearate gel or hydrogenated edible fats, emulsifying agents,for example lecithin, sorbitan monooleate, acacia; non-aqueous vehicles(which may include edible oils), for example almond oil, oily esterssuch as glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, ifdesired, conventional flavouring or colouring agents.

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions powders,solutions, pastes, gels, sprays, aerosols or oils and may containappropriate conventional additives such as preservatives, solvents toassist drug penetration and emollients in ointments and creams. Suchapplications include those to the eye or other external tissues, forexample the mouth and sin and the compositions are preferably applied asa topical ointment or cream. When formulated in an ointment, the activeingredient may be employed with either a paraffinic or a water miscibleointment base. Alternatively, the active ingredient may be formulated ina cream with an oil-in-water cream base or a water-in-oil base. Thecomposition may also contain compatible conventional carriers, such ascream or ointment bases and ethanol or oleyl alcohol for lotions.

Pharmaceutical compositions adapted for topical administration to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical compositions adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epiderma of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical compositions adapted for controlled or sustained releasemay be administered by injection, for example by the subcutaneous route.

Pharmaceutical compositions adapted for nasal administration wherein thecarrier is a solid include coarse powder having a particle size forexample in the range of 20-500 microns which is administered by rapidinhalation through the nasal passage from a container of the powder heldclose to the nose. Suitable compositions wherein the carrier is aliquid, for administration as a nasal spray or as nasal drops, includeaqueous or oil solutions of an active ingredient.

Pharmaceutical compositions adapted for administration by inhalationinclude fine particle dusts or mists which may be generated by means ofvarious types of metered dose pressurise aerosols, nebulizers orinsufflators.

Pharmaceutical compositions adapted for rectal administration may bepresented as suppositories or enemas. Suppositories will containconventional suppository bases, e.g. cocoa-butter or other glyceride.

Pharmaceutical compositions adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or spraycompositions.

Pharmaceutical compositions adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolution and suspensions may be prepared from sterile powders, granulesand tablets.

For parenteral administration, fluid unit dosage forms are preparedutilising the active ingredient and a sterile vehicle, water beingpreferred. The active ingredient, depending on the vehicle andconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the active ingredient can be dissolved in waterfor injection and filter sterilised before filling into a suitable vialor ampoule and sealing.

Modes of Administration

Described herein are compounds of Formula I or a pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.Also described, are pharmaceutical compositions comprising a compound ofFormulas I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof. The compounds and compositionsdescribed herein may be administered either alone or in combination withpharmaceutically acceptable carriers, excipients or diluents, in apharmaceutical composition, according to standard pharmaceuticalpractice.

Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include oral routes, intraduodenal routes,parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical,intrapulmonary, rectal administration, by implant, by a vascular stentimpregnated with the compound, and other suitable methods commonly knownin the art. For example, compounds described herein can be administeredlocally to the area in need of treatment. This may be achieved by, forexample, but not limited to, local infusion during surgery, topicalapplication, e.g., cream, ointment, injection, catheter, or implant,said implant made, e.g., out of a porous, non-porous, or gelatinousmaterial, including membranes, such as sialastic membranes, or fibers.The administration can also be by direct injection at the site (orformer site) of a tumor or neoplastic or pre-neoplastic tissue. Those ofordinary skill in the art are familiar with formulation andadministration techniques that can be employed with the compounds andmethods described herein, e.g., as discussed in Goodman and Gilman, ThePharmacological Basis of Therapeutics, current ed.; Pergamon; andRemington's, Pharmaceutical Sciences (current edition), Mack PublishingCo., Easton, Pa.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,intramedullary, intracardiac, intrathecal, intraspinal, intracapsular,subcapsular, intraorbital, intratracheal, subcuticular, intraarticular,subarachnoid, and intrasternal), intraperitoneal, transmucosal,transdermal, rectal and topical (including dermal, buccal, sublingual,intranasal, intraocular, and vaginal) administration although the mostsuitable route may depend upon for example the condition and disorder ofthe recipient. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. All methods include the step of bringing intoassociation a compound of the subject invention or a pharmaceuticallyacceptable salt, ester, prodrug or solvate thereof (“active ingredient”)with the carrier which constitutes one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both and then, if necessary, shapingthe product into the desired formulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders (e.g., povidone,gelatin, hydroxypropylmethyl cellulose), inert diluents, preservative,disintegrant (e.g., sodium starch glycolate, cross-linked povidone,cross-linked sodium carboxymethyl cellulose) or lubricating, surfaceactive or dispersing agents. Molded tablets may be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent. The tablets may optionally be coated or scored andmay be formulated so as to provide slow or controlled release of theactive ingredient therein. Tablets may optionally be provided with anenteric coating, to provide release in parts of the gut other than thestomach. All formulations for oral administration should be in dosagessuitable for such administration. The push-fit capsules can contain theactive ingredients in admixture with filler such as lactose, binderssuch as starches, and/or lubricants such as talc or magnesium stearateand, optionally, stabilizers. In soft capsules, the active compounds maybe dissolved or suspended in suitable liquids, such as fatty oils,liquid paraffin, or liquid polyethylene glycols. In addition,stabilizers may be added. Dragee cores are provided with suitablecoatings. For this purpose, concentrated sugar solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquersolutions, and suitable organic solvents or solvent mixtures. Dyestuffsor pigments may be added to the tablets or Dragee coatings foridentification or to characterize different combinations of activecompound doses.

Pharmaceutical preparations may be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, biocide, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Examples ofsuitable isotonic vehicles for use in such formulations include SodiumChloride Injection, Ringer's Solution, or Lactated Ringer's Injection.Suitable lipophilic solvents or vehicles include fatty oils such assesame oil, or synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes or other microparticulate systems may beused to target the compound to blood components or one or more organs.The concentration of the active ingredient in the solution may varywidely. Typically, the concentration of the active ingredient in thesolution is from about 1 ng/ml to about 10 μg/ml, for example from about10 ng/ml to about 1 μg/ml. Aqueous injection suspensions may containsubstances which increase the viscosity of the suspension, such assodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension may also contain suitable stabilizers or agents whichincrease the solubility of the compounds to allow for the preparation ofhighly concentrated solutions

Pharmaceutical preparations may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical preparations may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter, polyethyleneglycol, or other glycerides.

Pharmaceutical preparations may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof the present invention externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical preparations suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, suspensions, powders, solutions, spray,aerosol, oil, and drops suitable for administration to the eye, ear ornose. Alternatively, a formulation may comprise a patch or a dressingsuch as a bandage or adhesive plaster impregnated with activeingredients and optionally one or more excipients or diluents. Theamount of active ingredient present in the topical formulation may varywidely. The active ingredient may comprise, for topical administration,from 0.001% to 10% w/w, for instance from 1% to 2% by weight of theformulation. It may however comprise as much as 10% w/w but preferablywill comprise less than 5% w/w, more preferably from 0.1% to 1% w/w ofthe formulation.

Formulations suitable for topical administration in the mouth includelosenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient.

Pharmaceutical preparations for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Formulations

The compounds or compositions described herein can be delivered in avesicle, e.g., a liposome (see, for example, Langer, Science 1990, 249,1527-1533; Treat et al., Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Bernstein and Fidler, Ed., Liss, N.Y., pp. 353-365,1989). The compounds and pharmaceutical compositions described hereincan also be delivered in a controlled release system. In one embodiment,a pump may be used (see, Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al. Surgery, 1980 88, 507; Saudek et al. N. Engl. J.Med. 1989, 321, (574). Additionally, a controlled release system can beplaced in proximity of the therapeutic target. (See, Goodson, MedicalApplications of Controlled Release, 1984, Vol. 2, pp. 115-138). Thepharmaceutical compositions described herein can also contain the activeingredient in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be, for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, such asmicrocrystalline cellulose, sodium crosscarmellose, corn starch, oralginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be un-coatedor coated by known techniques to mask the taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, or cellulose acetate butyrate may be employed as appropriate.Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions may also be in the form of an oil-in-wateremulsions. The oily phase may be a vegetable oil, for example olive oilor arachis oil, or a mineral oil, for example liquid paraffin ormixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

Pharmaceutical compositions may be in the form of a sterile injectableaqueous solution. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. The sterile injectable preparation may also be a sterileinjectable oil-in-water microemulsion where the active ingredient isdissolved in the oily phase. For example, the active ingredient may befirst dissolved in a mixture of soybean oil and lecithin. The oilsolution then introduced into a water and glycerol mixture and processedto form a microemulsion. The injectable solutions or microemulsions maybe introduced into a patient's blood-stream by local bolus injection.Alternatively, it may be advantageous to administer the solution ormicroemulsion in such a way as to maintain a constant circulatingconcentration of the instant compound. In order to maintain such aconstant concentration, a continuous intravenous delivery device may beutilized. An example of such a device is the Deltec CADD-PLUS™ model5400 intravenous pump. The pharmaceutical compositions may be in theform of a sterile injectable aqueous or oleagenous suspension forintramuscular and subcutaneous administration. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

Pharmaceutical compositions may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the inhibitors with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing a compound or composition described herein can be used.As used herein, topical application can include mouth washes andgargles.

Pharmaceutical compositions may be administered in intranasal form viatopical use of suitable intranasal vehicles and delivery devices, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

Methods of Dosing and Treatment Regimens

The compounds of Formula I (including without limitation any of thecompounds specifically or generically described herein, including thecompounds presented in the tables) can be used in the preparation ofmedicaments for the treatment of leukotriene-dependent or leukotrienemediated diseases or conditions. In addition, a method for treating anyof the diseases or conditions described herein in a subject in need ofsuch treatment, involves administration of pharmaceutical compositionscontaining at least one compound of any of Formula I, or apharmaceutically acceptable salt, pharmaceutically acceptable N-oxide,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said subject

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. It is considered well within the skill of theart for one to determine such therapeutically effective amounts byroutine experimentation (including, but not limited to, a doseescalation clinical trial).

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. It is considered well within theskill of the art for one to determine such prophylactically effectiveamounts by routine experimentation (e.g., a dose escalation clinicaltrial). When used in a patient, effective amounts for this use willdepend on the severity and course of the disease, disorder or condition,previous therapy, the patient's health status and response to the drugs,and the judgment of the treating physician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days,and 365 days. The dose reduction during a drug holiday may be from10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be routinelydetermined in a manner known in the art according to the particularcircumstances surrounding the case, including, e.g., the specific agentbeing administered, the route of administration, the condition beingtreated, and the subject or host being treated. In general, however,doses employed for adult human treatment will typically be in the rangeof 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dosemay conveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds of Formula (G), Formula(G-I), and Formula (G-II), described herein are from about 0.01 to 2.5mg/kg per body weight. An indicated daily dosage in the larger mammal,including, but not limited to, humans, is in the range from about 0.5 mgto about 100 mg, conveniently administered in divided doses, including,but not limited to, up to four times a day or in extended release form.Suitable unit dosage forms for oral administration comprise from about 1to 50 mg active ingredient. The foregoing ranges are merely suggestive,as the number of variables in regard to an individual treatment regimeis large, and considerable excursions from these recommended values arenot uncommon. Such dosages may be altered depending on a number ofvariables, not limited to the activity of the compound used, the diseaseor condition to be treated, the mode of administration, the requirementsof the individual subject, the severity of the disease or conditionbeing treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Dosage Forms

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, cachet, pill, lozenge,powder or granule, sustained release formulations, solution, liquid,suspension, for parenteral injection as a sterile solution, suspensionor emulsion, for topical administration as an ointment, cream, lotions,sprays, foams, gel or paste, or for rectal or vaginal administration asa suppository or pessary. The pharmaceutical composition may be in unitdosage forms suitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc. Methods of preparingvarious pharmaceutical compositions with a specific amount of activecompound are known, or will be apparent, to those skilled in this art.For examples, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Ester, Pa., 18th Edition (1990).

Pharmaceutically acceptable carrier and/or diluent may include any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutical active substances is well knownin the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, use thereof in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

Dosage unit form refers to physically discrete units suited as unitarydosages for the mammalian subjects to be treated; each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. It is especially advantageous to formulateparenteral compositions in dosage unit form for ease of administrationand uniformity of dosage. The specification for the novel dosage unitforms described herein are dictated by and directly dependent on (a) theunique characteristics of the active material and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such as active material for the treatment ofdisease in living subjects having a diseased condition in which bodilyhealth is impaired.

The principal active ingredients are compounded for convenient andeffective administration in effective amounts with a suitablepharmaceutically acceptable carrier in dosage unit form. In the case ofcompositions containing supplementary active ingredients, the dosagesare determined by reference to the usual dose and manner ofadministration of the said ingredients.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch or other cellulosicmaterial, alginic acid and certain complex silicates and with bindingagents such as sucrose, gelatin and acacia. Additionally, lubricatingagents such as magnesium stearate, sodium lauryl sulfate and talc areoften useful for tableting purposes. Other reagents such as aninhibitor, surfactant or solubilizer, plasticizer, stabilizer, viscosityincreasing agent, or film forming agent may also be added. Solidcompositions of a similar type may also be employed in soft and hardfilled gelatin capsules. Preferred materials, therefore, include lactoseor milk sugar and high molecular weight polyethylene glycols. Whenaqueous suspensions or elixirs are desired for oral administration theactive compound therein may be combined with various sweetening orflavoring agents, coloring matters or dyes and, if desired, emulsifyingagents or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin, or combinations thereof.

Advantageously, agents such as local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe active ingredient is suspended in the vehicle instead of beingdissolved and sterilisation cannot be accomplished by filtration. Theactive ingredient can be sterilised by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the active ingredient.

In some embodiments, the pharmaceutical compositions according to theinvention are preferably adapted for oral administration.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions may also include other agentsconventional in the art having regard to the type of formulation inquestion, for example those suitable for oral administration may includeflavoring agents. They may also contain therapeutically active agents inaddition to the compounds of the present invention. Such carriers may bepresent as from about 1% up to about 98% of the formulation. Moreusually they will form up to about 80% of the formulation.

The compositions may contain from 0.1% by weight, preferably from 10-60%by weight, of the active material, depending on the method ofadministration.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per dose. Such aunit may contain for example 0.1 mg/kg to 750 mg/kg, more preferably 0.1mg/kg to 10 mg/kg depending on the condition being treated, the route ofadministration and the age, weight and condition of the patient.Preferred unit dosage compositions are those containing a daily dose orsub-dose, as herein above recited, or an appropriate fraction thereof,of an active ingredient.

It will be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of compounds in the first andsecond aspects described herein will be determined by the nature andextent of the condition being treated the form, route and site ofadministration, and the particular subject being treated, and that suchoptimums can be determined by conventional techniques. It will also beappreciated by one of skill in the art that the optimal course oftreatment, i.e., the number of doses of the aforementioned compoundsgiven per day for a defined number of days, can be ascertained by thoseskilled in the art using conventional course of treatment determinationtests.

Depending on the route of administration, the chemical compound orcomposition may be required to be coated in a material to protect itfrom the action of enzymes, acids and other natural conditions which mayinactivate it.

In order to administer the chemical compound or composition by otherthan parenteral administration, it may be coated by, or administeredwith, a material to prevent its inactivation. For example, it may beadministered in an adjuvant, co-administered with enzyme inhibitors orin liposomes. Adjuvant is used in its broadest sense and includes anyimmune stimulating compound such as interferon. Adjuvants contemplatedherein include resorcinols, non-ionic surfactants such aspolyoxyethylene oleyl ether and n-hexadecyl polyethylene ether.

Liposomes include water-in-oil-in-water CGF emulsions as well asconventional liposomes.

The active chemical compound or composition may also be administeredparenterally or intraperitoneally. Dispersions can also be prepared inglycerol, liquid polyethylene glycols, and mixtures thereof and in oils.Under ordinary conditions of storage and use, these preparations containa preservative.

The pharmaceutical compositions or formulations suitable for injectableuse include sterile aqueous solutions (where water soluble) ordispersions and sterile powders for the extemporaneous preparation ofsterile injectable solutions or dispersion. In all cases the form mustbe sterile and must be fluid to the extent that easy syringabilityexists. It must be stable under the conditions of manufacture andstorage and must be preserved against the contaminating action ofmicroorganisms such as bacteria. The carrier can be a solvent ordispersion medium containing, for example, water, ethanol, polyol (forexample, glycerol, propylene glycol, and liquid polyetheylene glycol,and the like), suitable mixtures thereof, and vegetable oils. The properfluidity can be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of superfactants.

Prolonged absorption of the injectable compositions can be brought aboutby the use in the compositions of agents delaying absorption, forexample, aluminium monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activechemical compound or composition in the required amount in theappropriate solvent with various of the other ingredients enumeratedabove, as required, followed by filtered sterilisation. Generally,dispersions are prepared by incorporating the sterilised activeingredient into a sterile vehicle which contains the basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, the preferred methods of preparation are vacuum drying andthe freeze-drying technique which yield a powder of the activeingredient plus any additional desired ingredient from previouslysterile-filtered solution thereof.

When the chemical compound or composition is suitably protected asdescribed above, it may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. The amount of active compound in such therapeuticallyuseful compositions is such that a suitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavouring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier.

Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets,pills, or capsules may be coated with shellac, sugar or both. A syrup orelixir may contain the active compound, sucrose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anydosage unit form should be pharmaceutically pure and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and formulations.

The methods described herein include inhibiting 1,3-β-D-glucan synthesisin a fungus by contacting the fungus with a composition containing anamount of a selective 1,3-β-D-glucan synthase (BGS) inhibitor compoundeffective for inhibiting synthesis of 1,3-β-D-glucan. A fungus may becontacted with the composition ex vivo or in vivo, e.g., to treat asubject suffering from a pathological fungal infection (e.g., aninvasive fungal infection). As used herein, “treating” or “treat” isintended to include preventing, ameliorating, curing, reducing fungalgrowth or reducing associated symptoms, or preventing any increase infungal growth or associated symptoms.

A subject in need of treatment with any of the compositions or methodsdescribed herein include, but are not limited to, a subject having afungal infection, or a subject at risk of developing a fungal infection.The subject may have been diagnosed as having such a fungal infection asdescribed herein or using standard medical techniques known to those ofskill in the art. For example, the plasma levels of (1→3)-β-D-glucan inserum can be assayed, where a serum level of (1→3)-β-D-glucan aboveabout 40, 50, 60, or 80 pg/ml indicates a likely infection by Candidaand Aspergillus. Alternatively, highly sensitive “pan-fungal” nucleicacid-based diagnostic assays can be used. See, e.g., Van Burik et al.(1998), J. of Clin. Microbiol, 36(5): 1169-1175; and Lau et al. (2007),J. of Clin. Microbiol. 45(2):380-385. In addition, such assays can beused to monitor the efficacy of treatment for a fungal infection. See,e.g., Kondori et al. (2004), Clinical and Diagnostic LaboratoryImmunology, 11(2):344-350. Alternatively a subject may exhibit one ormore symptoms of fungal infection.

A subject at risk of developing a fungal infection is a subject who hasbeen exposed to a fungus, or is susceptible to exposure to a fungus. Forinstance a subject that is susceptible to exposure to a fungus includesthose subjects who work with fungal material or in areas of high fungalcontent, subjects who travel to areas with high fungal infectivity ratesor are otherwise likely to be exposed to a fungal infection as well asthose subjects having particular susceptibility to fungal infectionresulting from medical conditions or therapies.

Examples of subjects having particular susceptibility to fungalinfections arising from medical conditions or therapies include but arenot limited to subjects who are immuncompromised. An immunocompromisedsubject is a subject that is incapable of inducing a normal effectiveimmune response or a subject that has not yet developed an immune system(e.g. preterm neonate). For example, the subject may beimmunocompromised due to AIDS (or AIDS treatment), cancer (or cancertreatment), severe combined immunodefficiency, ongoing treatment with animmunosuppressive agent, e.g., for suppression of organ transplantimmune rejection, or for treatment of an autoimmune, heteroimmune, orinflammatory condition.

In some cases, a subject in need of treatment for a fungal infection maybe suffering from tuberculosis, diabetes, severe burns, or intravenousdrug abuse. In other cases, the subject in need is undergoing prolongeduse of an intravenous or urinary catheter or is being subjected tochronic antibiotic exposure or chronic corticosteroid exposure.

Fungi whose growth can be inhibited by the compositions and methodsdescribed herein include, but are not limited to, moulds, e.g.,Aspergillus fumigatus, A. flavus, A. niger, A terreus, A flavus, Anidulans, A sydowi, Paecilomyces lilcinus, Fusarium solani, or, F.oxysporum, or Histoplasma capsulatum; and yeast, e.g., Candida aaseri,C. acidothermophilum, C. acutus, C. albicans, C. anatomiae, C. apis, C.apis var. galacta, C. atlantica, C. atmospherica, C. auringiensis, C.bertae, C. berthtae var. chiloensis, C. berthetii, C. blankii, C.boidinii, C. boleticola, C. bombi, C. bombicola, C. buinensis, C.butyri, C. cacaoi, C. cantarellii, C. cariosilignicola, C. castellii, C.castrensis, C. catenulata, C. chilensis, C. chiropterorum, C.coipomensis, C. dendronema, C. deserticola, C. diddensiae, C. diversa,C. entomaea, C. entomophila, C. ergatensis, C. ernobii, C. ethanolica,C. ethanothermophilum, C. famata, C. fluviotilis, C. fragariorum, C.fragicola, C. friedrichii, C. fructus, C. geochares, C. glabrata, C.glaebosa, C. gropengiesseri, C. guilliermondii, C. guilliermondii var.galactose, C. guilliermondii var. soya, C. haemulonii, C. halophila/C.versatilis, C. holmii, C. humilis, C. hydrocarbofumarica, C.inconspicua, C. insectalens, C. insectamans, C. intermedia, C. javanica,C. kefyr, C. krissii, C. krusei, C. krusoides, C. lambica, C.lusitaniae, C. magnoliae, C. maltosa, C. mamillae, C. maris, C.maritima, C. melibiosica, C. melinii, C. methylica, C. milleri, C.mogii, C. molischiana, C. montana, C. multis-gemmis, C. musae, C.naeodendra, C. nemodendra, C. nitratophila, C. norvegensis, C.norvegica, C. oleophila, C. oregonensis, C. osornensis, C. paludigena,C. parapsilosis, C. pararugosa, C. periphelosum, C. petrohuensis, C.petrophilum, C. philyla, C. pignaliae, C. pintolopesii var.pintolopesii, C. pintolopesii var. slooffiae, C. pinus, C. polymorphs,C. populi, C. pseudointermedia, C. quercitrasa, C. railenensis, C.rhagii, C. rugopelliculosa, C. rugosa, C. sake, C. salmanticensis, C.savonica, C. sequanensis, C. shehatae, C. silvae, C. silvicultrix, C.solani, C. sonorensis, C. sorbophila, C. spandovensis, C. sphaerica, C.stellata, C. succiphila, C. tenuis, C. terebra, C. tropicalis, C.utilis, C. valida, C. vanderwaltii, C. vartiovaarai, C. veronae, C.vini, C. wickerhamii, C. xestobii, C. zeylanoides, Saccharomycescerevisiae, Kluyveromyces lactis, or Schizosaccharomyces pombe.

Examples of fungal infections that can be treated with the compositionsand methods described herein described include, but are not limited to,blastomycosis, tinea, coccidiomycosis, cryptococcosis, candidiasis,moniliasis, dermatomycosis, dermatophytosis, favus, keratomycosis,phycomycosis, sporotrichosis, or rhinosporidiosis.

Combination Therapies

The compounds described herein or a pharmaceutically acceptable salt,prodrug, solvate, polymorph, tautomer or isomer thereof may beadministered as a sole therapy. The compounds described herein theirpharmaceutically acceptable salts, prodrug, solvates, polymorphs,tautomers or isomers may also be administered in combination withanother therapy or therapies. Combination treatments may occursequentially or concurrently and the combination therapies may beneoadjuvant therapies or adjuvant therapies.

In some embodiments, the compounds described herein can be administeredwith an additional therapeutic agent. In these embodiments, the compounddescribed herein can be in a fixed combination with the additionaltherapeutic agent or a non-fixed combination with the additionaltherapeutic agent.

By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds described herein ishypertension, then it may be appropriate to administer ananti-hypertensive agent in combination with the compound. Or, by way ofexample only, the therapeutic effectiveness of one of the compoundsdescribed herein may be enhanced by administration of anothertherapeutic agent, the overall therapeutic benefit to the patient isenhanced. Or, by way of example only, the benefit experienced by apatient may be increased by administering one of the compounds describedherein with another therapeutic agent (which also includes a therapeuticregimen) that also has therapeutic benefit. In any case, regardless ofthe disease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

Other therapies include, but are not limited to administration of othertherapeutic agents, radiation therapy or both. In the instances wherethe compounds described herein are administered with other therapeuticagents, the compounds described herein need not be administered in thesame pharmaceutical composition as other therapeutic agents, and may,because of different physical and chemical characteristics, beadministered by a different route. For example, thecompounds/compositions may be administered orally to generate andmaintain good blood levels thereof, while the other therapeutic agentmay be administered intravenously. The determination of the mode ofadministration and the advisability of administration, where possible,in the same pharmaceutical composition, is within the knowledge of theskilled clinician with the teachings described herein. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician. The particular choice of compound (and whereappropriate, other therapeutic agent and/or radiation) will depend uponthe diagnosis of the attending physicians and their judgment of thecondition of the patient and the appropriate treatment protocol.

Antifungal Compounds

Where a subject is in need of treatment for a fungal infection, any ofthe selective BGS inhibitor compounds described herein can be used incombination with a supplemental antifungal compound including, but notlimited to other echinocandin antifungal compounds (e.g., anidulafungin,caspofungin, or micafungin); polyene antifungal compounds (e.g.,natamycin, rimocidin, nystatin, or amphotericin B); imidazole antifungalcompounds (e.g., miconazole, ketoconazole, clotrimazole, econazole,bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole,sertaconazole, sulconazole, or tioconazole); triazole antifungalcompounds (e.g., fluconazole, itraconazole, isavuconazole ravuconazole,posaconazole, voriconazole, or terconazole); allylamines (e.g.,terbinafine, amorolfine, naftifine, or butenafine); and other antifungalcompounds such as ciclopirox olamine, 5-fluorocytosine, gentian violet,haloprogin, tolnaftate, or undecylenic acid.

Immunosuppressive Agents

Where a subject requires immunosuppressive therapy, any of the selectiveBGS inhibitor compounds described herein can be administered to thesubject prophylactically or therapeutically to treat a fungal infectionin combination with one or more immunosuppressive agents administered toinduce immunosuppression. Examples of immunosuppressive agents include,but are not limited to, corticosteroids, cyclophosphamide, folic acidanalogues, methotrexate, purine analogues, azathioprine, mercaptopurine,methotrexate, dactinomycin, anthracyclines, mitomycin c, bleomycin,mithramycin, IL-2 receptor antibodies, CD3 directed antibodies, OKT33(R), anti-CD3 antibody, anti-CD25 antibodies, tacrolimus, cyclosporin,tacrolimus, rapamicin, ifn-β, ifn-γ, infliximab, etanercept, adalimumab,curcumin, catechins, mycophenolic acid, or FTY720.

Chemotherapy Agents

Where a subject is suffering from a cancer, any of the selective BGSinhibitor compounds described herein can be administered to the subjectprophylactically or therapeutically to treat a fungal infection incombination with one or more chemotherapy agents administered to treatthe cancer. Examples of chemotherapy agents include, but are not limitedto, any of the following: 5-aza-2′-deoxycytidine, all trans retinoicacid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib(Gleevec®), 17-n-allylamino-17-demethoxygeldanamycin (17-aag),flavopiridol, ly294002, bortezomib, trastuzumab, bay 11-7082, pkc412,pd184352, paclitaxel, adriamycin, dactinomycin, bleomycin, vinblastine,cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine;adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate;aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin hydrochloride; droloxifene; droloxifene citrate;dromostanolone propionate; duazomycin; edatrexate; eflornithinehydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;estramustine; estramustine phosphate sodium; etanidazole; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine;fosquidone; fostriecin sodium; gemcitabine hydrochloride; hydroxyurea;idarubicin hydrochloride; ifosfamide; iimofosine; interleukins,interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecanhydrochloride; lanreotide acetate; letrozole; leuprolide acetate;liarozole hydrochloride; lometrexol sodium; lomustine; losoxantronehydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride;megestrol acetate; melengestrol acetate; melphalan; menogaril;mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide;safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vindesine; vindesinesulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate;vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate;vorozole; zeniplatin; zinostatin; or zorubicin hydrochloride.

Anti-Inflammatory Agents

Where a subject is suffering from an inflammatory condition, any of theselective BGS inhibitor compounds described herein can be administeredto the subject prophylactically or therapeutically to treat a fungalinfection in combination with one or more anti-inflammatory compoundsadministered to treat the inflammatory condition. Examples ofanti-inflammatory agents include, but are not limited to, amcinolide,betamethosone diproprionate, budesonide, clobetasol, clocortolone,dexamethasone, diflorasone, dutasteride, flumethasone pivalate,flunisolide, fluocinolone acetonide, fluocinonide, fluorometholone,fluticasone propionate, fluradrenolide, hydroflumethiazide, aspirin,amoxiprin, benorilate, choline magnesium salicylate, diflunisal,faislamine, methyl salicylate, magnesium salicylate, and salicylsalicylate (salsalate); arylalkanoic acids, e.g., diclofenac,aceclofenac, acemetacin, bromfenac, etodolac, indometacin, nabumetone,sulindac, and tolmetin; 2-arylpropionic acids (profens), e.g., ibuprofencarprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, ketorolac,loxoprofen, naproxen, tiaprofenic acid, and suprofen; n-arylanthranilicacids (fenamic acids), e.g., mefenamic acid and meclofenamic acid;pyrazolidine derivatives, e.g., phenylbutazone, azapropazone,metamizole, oxyphenbutazone, and sulfinprazone; oxicams, e.g.,piroxicam, lornoxicam, meloxicam, and tenoxicam; cox-2 inhibitors, e.g.,etoricoxib, lumiracoxib, and parecoxib; sulphonanilides such asnimesulide; or other non-steroidal anti-inflammatory agents, e.g.,licofelone and omega-3 fatty acids.

Antibiotics

Where a subject is suffering from a bacterial infection, any of theselective BGS inhibitor compounds described herein can be administeredto the subject prophylactically or therapeutically to treat a fungalinfection in combination with one or more antibiotic compounds agentsadministered to treat the bacterial infection. Examples of antibioticsinclude, but are not limited to, amikacin, gentamicin, kanamycin,neomycin, netilmicin, streptomycin, tobramycin, geldanamycin,herbimycin, loracarbef, ertapenem, imipenem/cilastatin, meropenem,cefadroxil, cefazolin, cephalexin, cefaclor, cefamandole, cefoxitin,cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone,cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefepime, teicoplanin, vancomycin, azithromycin,clarithromycin, dirithromycin, erythromycin, roxithromycin,troleandomycin, aztreonam, amoxicillin, ampicillin, azlocillin,carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin,nafcillin, penicillin, piperacillin, ticarcillin, bacitracin, colistin,polymyxin b, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin,lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin,mafenide, prontosil (archaic), sulfacetamide, sulfamethizole,sulfanilimide (archaic), sulfasalazine, sulfisoxazole, trimethoprim,trimethoprim-sulfamethoxazole (co-trimoxazole) (tmp-smx),demeclocycline, doxycycline, minocycline, oxytetracysline, tetracycline,arsphenamine, chloramphenicol, clindamycin, ethambutol, fosfomycin,fusidic acid, furazolidone, isoniazid, linezolid, metronidazole,mupirocin, nitrofurantoin, platensimycin, pyrazinamide,quinupristin/dalfopristin, rifampin, spectinomycin, or telithromycin.

Anti-HIV Compounds

Where a subject is suffering from an HIV infection (e.g., suffering fromAIDS), any of the selective BGS inhibitor compounds described herein canbe administered to the subject prophylactically or therapeutically totreat a fungal infection in combination with one or more anti-HIVcompounds administered to treat the HIV infection. Examples of anti-HIVcompounds include, but are not limited to, AZT (zidovudine, Retrovir),ddI (didanosine, Videx), 3TC (lamivudine, Epivir), d4T (stavudine,Zerit), abacavir (Ziagen), and FTC (emtricitabine, Emtriva), tenofovir(Viread), efavirenz (Sustiva), nevirapine (Viramune),lopinavir/ritonavir (Kaletra), indinavir (Crixivan), ritonavir (Norvir),nelfinavir (Viracept), saquinavir hard gel capsules (Invirase),atazanavir (Reyataz), amprenavir (Agenerase), fosamprenavir (Telzir),tipranavir (Aptivus), or T20 (enfuvirtide, Fuzeon).

Anti-Diabetic Agents

Where a subject is suffering from diabetes, any of the selective BGSinhibitor compounds described herein can be administered to the subjectprophylactically or therapeutically to treat a fungal infection incombination with one or more anti-diabetic agents compounds administeredto treat the diabetes. Examples of antidiabetic agents include, but notlimited to, insulin secretagogues, insulin sensitizers, biguanides,sulfonyl ureas, glucosidase inhibitors, peroxisome proliferatoractivated receptor (PPAR) γ agonists, such as thiazolidinediones, PPAR αagonists such as fibric acid derivatives, aP2 inhibitors, dipeptidylpeptidase IV (DP4) inhibitors, sodium-glucose co-transporter type 2(SGLT2) inhibitors, meglitinides, insulin, glucagon-like peptide-1(GLP-1), GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (7-37) (asdisclosed in U.S. Pat. No. 5,614,492, as well as AC2993, LY-315902,metformin, phenformin or glyburide (also known as glibenclamide),glimepiride (disclosed in U.S. Pat. No. 4,379,785), glipizide,gliclazide or chlorpropamide, acarbose (disclosed in U.S. Pat. No.4,904,769), miglitol (disclosed in U.S. Pat. No. 4,639,436),troglitazone (disclosed in U.S. Pat. No. 4,572,912), rosiglitazone,pioglitazone, MCC-555 (disclosed in U.S. Pat. No. 5,594,016), GL-262570,englitazone, darglitazone, isaglitazone, JTT-501, L-895645, R-119702,N,N-2344, YM-440, AR-H039242 GW-409544, or KRP297.

Kits

The compounds, compositions and methods described herein provide kitsfor the treatment of disorders, such as the ones described herein. Thesekits comprise a compound, compounds or compositions described herein ina container and, optionally, instructions teaching the use of the kitaccording to the various methods and approaches described herein. Suchkits may also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, disease statefor which the composition is to be administered, or other informationuseful to the health care provider. Such information may be based on theresults of various studies, for example, studies using experimentalanimals involving in vivo models and studies based on human clinicaltrials. Kits described herein can be provided, marketed and/or promotedto health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits may also, in some embodiments,be marketed directly to the consumer. The packaging material maycomprise a container for housing the composition and optionally a labelaffixed to the container. The kit may also optionally compriseadditional components, such as syringes for administration of thecomposition. The kit may comprise the composition in single or multipledose forms.

The compounds described herein can be utilized for diagnostics and asresearch reagents. For example, the compounds described herein, eitheralone or in combination with other compounds, can be used as tools indifferential and/or combinatorial analyses to elucidate expressionpatterns of genes expressed within cells and tissues. As onenon-limiting example, expression patterns within cells or tissuestreated with one or more compounds are compared to control cells ortissues not treated with compounds and the patterns produced areanalyzed for differential levels of gene expression as they pertain, forexample, to disease association, signaling pathway, cellularlocalization, expression level, size, structure or function of the genesexamined. These analyses can be performed on stimulated or unstimulatedcells and in the presence or absence of other compounds which affectexpression patterns.

Besides being useful for human treatment, the compounds and formulationsof the present invention are also useful for veterinary treatment ofcompanion animals, exotic animals and farm animals, including mammals,rodents, and the like. More preferred animals include horses, dogs, andcats.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemic

EXAMPLES

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. The experimental procedures togenerate the data shown are discussed in more detail below. Theinvention has been described in an illustrative manner, and it is to beunderstood that the terminology used is intended to be in the nature ofdescription rather than of limitation.

I. Chemical Syntheses

Compounds according to the invention may be prepared by any suitablemethod known in the art. Exemplary methods for making the compounds inaccordance with the invention are shown below. It should be understoodthat the following are provided for exemplary purposes and additionalcompounds and compounds with additional substitutions are contemplatedby the present invention. Also, where a substituent is exemplified onone compound, it should be understood that that substituent could alsobe attached to any of the other compounds described herein.

Example 1 was prepared according to Scheme 1.

Example 1 Synthesis of(E)-N-[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-N-(4-phenoxyphenyl)-3-phenylacrylamide(OGT4344) Compound 1 (Intermediate):{(4-Bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid, methyl ester

(4-Bromophenylamino)acetic acid, methyl ester (8.74 g, 0.036 mol) wastreated with cinnamoyl chloride (11.99 g, 0.072 mol) in pyridine (50 mL)in the presence of 4-dimethylaminopyridine (0.489 g, 0.004 mol). Thereaction mixture was stirred at room temperature for 2 h. The crudeproduct was purified by flash column chromatography on silica gel,eluting with ethyl acetate/dichloromethane (1:20), to give the titlecompound as a white crystalline solid (13.13 g, 98%). ¹HNMR (300 MHz)(CDCl₃) δ 3.67 (3H, s), 4.42 (2H, s), 6.28 (1H, d, J=16 Hz), 7.19 (2H,d), 7.2-7.3 (5H, m), 7.51 (2H, d) and 7.66 (1H, d, J=16 Hz).

Compound 2 (Intermediate):{(4-Bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid

A solution of {(4-bromophenyl)-[(E)-(3-phenylacryloyl)]amino}aceticacid, methyl ester 1 (14.61 g, 0.39 mol) in THF (150 mL) and methanol(50 mL) was treated with lithium hydroxide (2.80 g, 0.117 mol) in water(50 mL). The reaction mixture was stirred at room temperature for 45 minand then acidified with conc. hydrochloric acid and concentrated invacuo. The residue was diluted with ethyl acetate and washed with 10%hydrochloric acid, brine, dried (Na₂SO₄) and the organic solutionevaporated to give the title compound as a viscous oil (13.82 g, 97%).¹HNMR (300 MHz) (CDCl₃) δ 4.53 (2H, s), 6.36 (1H, d, J=16 Hz), 7.27 (2H,d), 7.3-7.4 (5H, m), 7.60 (2H, d) and 7.76 (1H, d, J=16 Hz).

Compound 3 (Intermediate):[(S)-1-(2-{(4-Bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester

1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (9.39 g, 0.049 mol) wasadded to a solution of{(4-Bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid 2 (13.82 g,0.038 mol), (3S)-(+3-(tert-butoxycarbonylamino)pyrrolidine (9.13 g,0.049 mol), 1-hydroxy-7-azabenzotriazole (6.67 g, 0.049 mol) andN-methylmorpholine (8.4 mL, 0.08 mol) in DMF (150 mL). The reactionmixture was stirred at room temperature for 16 h and then concentratedin vacuo. The residue was diluted with ethyl acetate and washed with 10%hydrochloric acid (×3), brine, saturated aqueous sodium bicarbonate (×2)and brine. The title compound began to crystallize during work-up andwas collected by filtration. The mother liquor was concentrated toprovide a further quantity of product. Total yield of title compound:17.43 g, 86%. ¹HNMR (300 MHz) (CDCl₃) δ 1.45 (6H, s), 1.60 (3H, s),1.7-2.3 (2H, m), 3.4-3.8 (4H, m), 4.1-4.9 (3H, m), 6.36 (1H, d, J=16Hz), 7.36 (2H, d), 7.2-7.4 (5H, m), 7.55 (2H, d) and 7.70 (1H, d, J=16Hz).

Compound 4 (Intermediate):[(S)-1-(2-{[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester

DMF (20 mL) was added to a mixture of[(S)-1-(2-{(4-bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester 3 (2.00 g, 3.78 mmol), potassium acetate (1.11 g,11.3 mmol), palladium[II]acetate (25 mg, 0.113 mmol) andbis(pinacolato)diboron (1.15 g, 4.54 mmol). The reaction mixture wasstirred and degassed and then argon was bubbled through. The mixture washeated at 85° C. under argon, with stirring, for 5.5 h. The reaction wasdiluted with ethyl acetate and washed with 10% hydrochloric acid (×2),brine, dried (Na₂SO₄) and evaporated to dryness. The residue waspurified by flash column chromatography on silica gel, eluting withethyl acetate, to give the title compound as an oil (1.85 g, 71%). ¹HNMR(300 MHz) (CDCl₃) δ 1.36 (12H, s), 1.45 (6H, s), 1.58 (3H, s), 1.7-2.3(2H, m), 3.4-3.8 (3H, m), 4.2-4.9 (2H, m), 6.43 (1H, d, J=16 Hz),7.23-7.37 (5H, m), 7.45 (2H, d), 7.70 (1H, d, J=16 Hz) and 7.86 (2H, d).

Compound 5:[(S)-1-(2-{(4-Borono-phenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester

Sodium periodate (2.06 g, 9.6 mmol) and ammonium acetate (0.74 g, 9.6mmol) in water (20 mL) were added to[(S)-1-(2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]-carbamicacid, tert-butyl ester 4 (1.85 g, 3.2 mmol) in acetone (30 mL) and thereaction stirred at room temperature for 64 h. The reaction mixture wasconcentrated in vacuo and 1M NaOH was added. The mixture was stirred for4 h and then shaken with dichloromethane and filtered. The two layerswere separated and the NaOH layer washed with dichloromethane. Theaqueous basic layer was acidified to pH1 with conc. hydrochloric acidand extracted with ethyl acetate (×2). The combined organic layers werewashed with brine, dried (Na₂SO₄) and evaporated to dryness. Theresultant residue was purified by flash column chromatography on silicagel, eluting with ethyl acetate→5% methanol/ethyl acetate→10%methanol/ethyl acetate→methanol, to give the title compound as a glass(1.26 g, 80%) which was used directly in the next stage.

Compound 6:[(S)-1-(2-{(4-Phenoxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester

Triethylamine (0.13 mL, 0.91 mmol) was added to[(S)-1-(2-{(4-borono-phenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester 5 (90 mg, 0.18 mmol), copper[II]acetate, 4A sieve(powdered) and phenol (26 mg, 0.27 mmol) in dichloromethane (4 mL). Thereaction mixture was stirred at room temperature for 16 h and thendiluted with dichloromethane and washed with 10% hydrochloric acid, 1MNaOH (×2) and brine, dried (Na₂SO₄) and evaporated to dryness. Theresidue was purified by column chromatography on silica gel, elutingwith ethyl acetate/petrol (2:1), to give the title compound as a whitepowder (60 mg) which was used directly in the next stage.

Compound 7:(E)-N-[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-N-(4-phenoxyphenyl)-3-phenylacrylamide(OGT4344)

Trifluoroacetic acid (2 mL) was added to a solution of[(S)-1-(2-{(4-phenoxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester 6 (60 mg) in dichloromethane (6 mL). The reactionmixture was stirred at room temperature for 30 min, and thenconcentrated in vacuo. The residue was dissolved in ethyl acetate,washed with 1M NaOH, (×2), brine, dried (Na₂SO₄) and evaporated todryness. The resultant residue was purified by column chromatography onsilica gel, eluting with ethyl acetate/methanol/ammonium hydroxide(90:5:5) to give the title compound (10 mg). ¹HNMR (300 MHz) (CDCl₃) δ1.6-2.3 (2H, m), 3.15-3.75 (5H, m), 4.40 (2H, m), 6.43 (1H, d, J=16 Hz),7.02 (2H, d), 7.06 (2H, d), 7.15 (1H, t), 7.25-7.45 (9H, m) and 7.69(1H, d, J=16 Hz).

Examples 2-4 were prepared according to Scheme 2.

Trifluoroacetic acid (30 mL) was added to a solution of[(S)-1-(2-{(4-bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester 3 (4.0 g, 7.57 mmol) in dichloromethane (90 mL).The reaction mixture was stirred at room temperature for 16 h, and thenconcentrated in vacuo. The residue was dissolved in ethyl acetate,washed with 1M NaOH (×2), brine, dried (Na₂SO₄) and evaporated to givethe title compound as a foam (2.78 g, 86%). ¹HNMR (300 MHz) (d6-DMSO) δ1.5-2.1 (2H, 4×m), 3.08 (1H, m), 3.1-3.6 (4H, m), 4.47, 4.50 (2H, 2×brs), 6.43 (1H, br d), 7.3-7.5 (7H, m), 7.53 (1H, d, J=16 Hz) and 7.65(2H, d).

Example 3 Synthesis of(E)-N-[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-3-phenyl-N-(3′-trifluoromethoxy-biphenyl-4-yl)-acrylamide(OGT4325) Compound 9

Tetrakis(triphenylphosphine)palladium[0] (20 mg, 5 mol %) was added inone portion to(E)-N-[2-((S)-3-aminopyrrolidin-1-yl)-2-oxo-ethyl]-N-(4-bromo-phenyl)-3-phenylacrylamide8 (150 mg, 0.353 mmol) and 3-trifluoromethoxy-phenylboronic acid (1.5eq) in dioxane (2 mL) followed by 1M aqueous Na₂CO₃ (0.7 mL). Thereaction mixture was heated at 150° C. in a microwave reactor for 20min. It was then diluted with ethyl acetate, washed with 10% NaOH, brineand water and filtered through a pad of celite. The filtrate was dried(Na₂SO₄) and evaporated to dryness. The resultant residue was purifiedby silica gel column chromatography, eluting withdichloromethane/methanol/chloroform (93:5:2), to give the title compound(160 mg, 89%). ¹HNMR (300 MHz) (CDCl₃) δ 1.60-2.25 (2H, m), 3.15-3.40(1H, m), 3.50-3.80 (4H, m), 4.40-4.65 (2H, m), 6.48 (1H, d, J=16 Hz),7.20-7.36 (7H, m), 7.45 (1H, br s), 7.49 (1H, d), 7.54 (3H, m), 7.62(2H, d) and 7.72 (1H, d, J=16 Hz).

Example 4 Synthesis of4′-{[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-[(E)-(3-phenylacryloyl)]-amino}-biphenyl-3-carboxylicacid, ethyl ester (OGT4355) Compound 10

This compound was prepared from(E)-N-[2-((S)-3-aminopyrrolidin-1-yl)-2-oxo-ethyl]-N-(4-bromophenyl)-3-phenylacrylamide(44%) by the same method as described for compound 9. ¹HNMR (300 MHz)(CDCl₃) δ 1.42 (3H, t), 1.65-2.25 (2H, m), 3.20-3.40 (1H, m), 3.50-3.80(4H, m), 4.42 (2H, q), 4.45-4.65 (2H, m), 6.49 (1H, d, J=16 Hz),7.25-7.40 (5H, m), 7.50-7.60 (3H, m), 7.67 (2H, d), 7.73 (1H, d, J=16Hz), 7.80 (1H, d), 8.06 (1H, d) and 8.30 (1H, br s).

Examples 5 and 6 were synthesized according to Scheme 3.

Compound 11 (Intermediate): (E)-3-Phenylacrylic acid4-[(E)-(3-phenylacryloyl)amino]phenyl ester

Cinnamoyl chloride (16.79 g, 100.8 mmoL) was added to a solution of4-aminophenol (5.00 g, 45.8 mmol) and DMAP (0.56 g, 4.58 mmol) inpyridine (50 mL). The reaction mixture was stirred at room temperaturefor 30 min whereupon a solid mass formed. Dichloromethane (50 mL) wasadded and the resultant suspension was stirred at room temperature for 2h. The reaction mixture was poured into 10% hydrochloricacid/dichloromethane and shaken. The precipitated white solid wasremoved by filtration, washed with dichloromethane, 10% hydrochloricacid and then dichloromethane again. The organic layer of the filtratewas separated and washed with 10% hydrochloric acid (×2) and brine,dried (Na₂SO₄) and evaporated to give the title compound (15.1 g, 89%).¹HNMR (300 MHz) (CDCl₃) δ 6.55 (1H, d, J=16 Hz), 6.64 (1H, d, J=16 Hz),7.18 (2H, d), 7.35-7.45 (6H, m), 7.58 (4H, m), 7.67 (2H, m), 7.78 (1H,d, J=16) and 7.88 (1H, d, J=16).

Compound 12 (Intermediate): (E)-3-Phenylacrylic acid4-{methoxycarbonylmethyl-[(E)-(3-phenylacryloyl)]-amino}phenyl ester

Sodium hydride (60%, 162 mg, 4.06 mmol) was washed with anhydrous THF(×2) and then suspended in anhydrous THF (20 mL). To this was added(E)-3-phenylacrylic acid 4-[(E)-(3-phenylacryloyl)amino]phenyl ester 11(1.00 g, 2.71 mmol) followed by methyl bromoacetate (0.51 mL, 5.41mmol). The reaction mixture was stirred at room temperature for 3 days.It was then diluted with ethyl acetate and washed with brine (×3), dried(Na₂SO₄) and evaporated. The resultant residue was purified by flashcolumn chromatography on silica gel, eluting with petrol/ethyl acetate(2:1 →1:1) and then ethyl acetate, to afford the title compound (0.734g, 61%). ¹HNMR (300 MHz) (CDCl₃) δ 3.77 (3H, s), 4.52 (2H, s), 6.43 (1H,d, J=16 Hz), 6.65 (1H, d, J=16 Hz), 7.25-7.40 (7H, m), 7.45 (4H, m),7.61 (3H, m), 7.75 (1H, d, J=16 Hz) and 7.91 (1H, d, J=16 Hz).

Compound 13 (Intermediate):{(4-Hydroxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid

Lithium hydroxide (119 mg, 4.96 mmol) in water (10 mL) was added to asolution of (E)-3-phenylacrylic acid4-{methoxycarbonylmethyl-[(E)-(3-phenylacryloyl)]-amino}phenyl ester 12(734 mg, 1.66 mmol) in THF (30 mL) and methanol (10 mL). The reactionmixture was stirred at room temperature for 2 h. A further quantity oflithium hydroxide (119 mg, 4.96 mmol) in water (5 mL) was added and thereaction mixture stirred for a further 1 h. It was then acidified to pH1with conc. hydrochloric acid and concentrated in vacuo. The aqueousmixture was extracted with ethyl acetate (×2) and the organic layerscombined, washed with brine, dried (Na₂SO₄) and evaporated. Theresultant residue was purified by flash column chromatography on silicagel, eluting with ethyl acetate, to afford the title compound (0.37 g,75%). ¹HNMR (300 MHz) (d6-DMSO) δ 4.07 (2H, br s), 6.37 (1H, d, J=15Hz), 6.78 (2H, d), 7.22 (2H, d), 7.34 (5H, m) and 7.44 (1H, d, J=15 Hz).

Compound 14 (Intermediate):[(S)-1-(2-{(4-Hydroxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester

1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.36 g, 1.87 mmol) wasadded to a solution of{(4-hydroxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid 13 (0.37 g,1.24 mmol), 1-hydroxy-7-azabenzotriazole (0.25 g, 1.87 mmol),(3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (0.35 g, 1.87 mmol) andN-methyl-morpholine (0.27 mL, 2.5 mmol) in DMF (40 mL). The reactionmixture was stirred at room temperature for 3 days and then diluted withethyl acetate and washed with 10% hydrochloric acid (×2), brine, NaHCO₃(×2) and brine, dried (Na₂SO₄) and evaporated. The residue was purifiedby column chromatography on silica gel, eluting with ethylacetate/petrol (4:1)→ethyl acetate, to give the title compound as awhite powder (0.419 g, 72%). ¹HNMR (300 MHz) (CDCl₃) δ 1.45 (9H, s),1.8-2.25 (2H, m), 3.4-3.8 (4H, m), 4.15 (1H, m), 4.6 (1H, m), 5.3 (1H,m), 6.43 (1H, d, J=16), 6.87 (2H, d), 7.2-7.32 (7H, m) and 7.65 (1H, d,J=16 Hz).

Compound 15:[(S)-1-(2-{[4-(3,4-Dichlorobenzyloxy)phenyl]-[(E)-(3-phenylacryloyl)]amino}-acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester

3,4-Dichlorobenzyl chloride (15 μL) was added to a mixture of[(S)-1-(2-{(4-hydroxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester 14 (50 mg, 0.11 mmol), cesium carbonate (52 mg,0.16 mmol) and TBAI (40 mg, 0.11 mmol) in DMF (3 mL). The reactionmixture was stirred at room temperature overnight and then diluted withethyl acetate and washed with 10% hydrochloric acid (×2) and brine,dried (Na₂SO₄) and evaporated to dryness. The residue was purified byflash column chromatography on silica gel, eluting with ethylacetate/petrol (2:1), to afford the title compound as a colourless foam(46 mg, 68%). ¹HNMR (300 MHz) (CDCl₃) δ 1.41 (9H, s), 1.7-2.2 (2H, m),3.35-3.8 (4H, m), 4.15-4.35 (2H, m), 4.5 (1H, m), 4.7-4.9 (1H, m), 5.01(2H, s), 6.35 (1H, d, J=16 Hz), 6.93 (2H, d), 7.2-7.3 (6H, m), 7.37 (2H,d), 7.44 (1H, d), 7.52 (1H, br s) and 7.64 (1H, d, J=16 Hz).

Compound 16:[(S)-1-(2-{[4-(4-Trifluoromethoxybenzyloxy)phenyl]-[(E)-(3-phenylacryloyl)]-amino}acetyl)pyrrolidin-3-yl]carbamicacid, tert-butyl ester

4-Trifluoromethoxybenzyl bromide (17 μL) was added to a mixture of[(S)-1-(2-{(4-hydroxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]-carbamicacid, tert-butyl ester 14 (50 mg, 0.11 mmol), cesium carbonate (52 mg,0.16 mmol) and TBAI (40 mg, 0.11 mmol) in DMF (3 mL). The reactionmixture was stirred at room temperature overnight and then diluted withethyl acetate and washed with 10% hydrochloric acid (×2) and brine,dried (Na₂SO₄) and evaporated to dryness. The residue was purified byflash column chromatography on silica gel, eluting with ethylacetate/petrol (2:1) to afford the title compound as a colourless foam(52 mg, 75%). ¹HNMR (300 MHz) (CDCl₃) 1.41 (9H, s), 1.7-2.2 (2H, m),3.35-3.8 (4H, m), 4.15-4.35 (2H, m), 4.5 (1H, m), 4.7-4.9 (1H, m), 5.00(2H, s), 6.37 (1H, d, J=16 Hz), 6.95 (2H, d), 7.18-7.30 (7H, m), 7.32(2H, d), 7.45 (2H, d) and 7.64 (1H, d, J=16 Hz).

Example 5 Synthesis of(E)-N-[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-N-[4-(3,4-dichloro-benzyloxy)phenyl]-3-phenylacrylamide(OGT4421) Compound 17

Trifluoroacetic acid (2 mL) was added to a solution of[(S)-1-(2-{[4-(3,4-dichlorobenzyloxy)phenyl]-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]-carbamicacid, tert-butyl ester 15 (46 mg) in dichloromethane (6 mL). Thereaction mixture was stirred at room temperature for 50 min and thenconcentrated in vacuo. The residue was dissolved in dichloromethane,washed with 1M NaOH (×2), brine, dried (Na₂SO₄) and evaporated to givethe title compound as a foam (26 mg, 68%). ¹HNMR (300 MHz) (CDCl₃) δ1.5-1.8 (1H, m), 1.95-2.2 (1H, m), 3.1-3.3 (1H, m), 3.45-3.75 (4H, m),4.34 (1H, dd), 4.48 (1H, t), 5.01 (2H, s), 6.36 (1H, d, J=16 Hz), 6.93(2H, m), 7.20-7.32 (6H, m), 7.38 (2H, d), 7.44 (1H, d), 7.52 (1H, br s)and 7.64 (1H, d, J=16 Hz).

Example 6 Synthesis of(E)-N-[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-N-[4-(4-trifluoromethoxy-benzyloxy)phenyl]-3-phenylacrylamide(OGT4420) Compound 18

Trifluoroacetic acid (2 mL) was added to a solution of[(S)-1-(2-{[4-(4-trifluoromethoxybenzyloxy)phenyl]-[(E)-(3-phenylacryloyl)]amino}acetyl)-pyrrolidin-3-yl]carbamicacid, tert-butyl ester 16 (52 mg) in dichloromethane (6 mL). Thereaction mixture was stirred at room temperature for 50 min and thenconcentrated in vacuo. The residue was dissolved in dichloromethane,washed with 1M NaOH (×2), brine, dried (Na₂SO₄) and evaporated to givethe title compound as a foam (40 mg, 91%). ¹HNMR (300 MHz) (CDCl₃) δ1.5-1.8 (1H, m), 1.95-2.2 (1H, m), 3.1-3.3 (1H, m), 3.45-3.75 (4H, m),4.34 (1H, dd), 4.48 (1H, t), 5.05 (2H, s), 6.37 (1H, d, J=16 Hz), 6.95(2H, m), 7.18-7.32 (7H, m), 7.38 (2H, d), 7.45 (2H, d) and 7.65 (1H, d,J=16 Hz).

Examples 7, 8 and 9 were synthesized according to Scheme 4.

Compound 19 (Intermediate): [Carboxymethyl-(4-phenoxyphenyl)amino]aceticacid

Lithium hydroxide (6.23 g, 0.26 mol) in water (50 mL) was added to asolution of [carboxymethyl-(4-phenoxyphenyl)amino]acetic acid,bis-methyl ester (17.05 g, 0.052 mol) in THF (150 mL) and methanol (50mL). The reaction mixture was stirred at room temperature for 2 h,acidified to pH 1 with concentrated sulfuric acid and then concentratedin vacuo. The residue was extracted with ethyl acetate and the organiclayer washed with 10% hydrochloric acid, brine, dried (Na₂SO₄) andevaporated to dryness. The crude product was recrystallised from ethylacetate/petrol to give the title compound as a white solid (11.30 g,73%). ¹HNMR (300 MHz) (d6-DMSO) δ 4.10 (4H, s), 6.55 (2H, d), 6.87 (2H,d), 6.92 (2H, d), 7.02 (1H, t) and 7.31 (2H, t).

Compound 20 (Intermediate):[[2-((S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(4-phenoxy-phenyl)amino]aceticacid

A mixture of [carboxymethyl-(4-phenoxyphenyl)amino]acetic acid 19 (0.5g, 1.66 mmol) in acetic anhydride (10 mL) was heated to reflux withstirring for 45 minutes. The reaction mixture was cooled to roomtemperature and poured into saturated aqueous sodium bicarbonate. Solidsodium bicarbonate was added and the mixture stirred until effervescencehad ceased. The aqueous mixture was extracted with ethyl acetate (×2)and the organic fractions combined, washed with saturated aqueous sodiumbicarbonate, brine, dried (Na₂SO₄) and evaporated to dryness. Theresidue was co-evaporated with toluene, dissolved in THF (10 mL) andadded to (35)-(+3-(tert-butoxycarbonylamino)pyrrolidine (0.39 g, 2.09mmol). The reaction mixture was stirred for 3 days and then concentratedin vacuo. The residue was diluted with ethyl acetate and washed with 10%hydrochloric acid (×2), brine, dried (Na₂SO₄) and evaporated to dryness.The crude product was crystallized from ethyl acetate to give the titlecompound as a cream powder (0.35 g, 45%). ¹HNMR (300 MHz) (CDCl₃) δ 1.45(6H, s), 1.55 (3H, s), 1.8-2.4 (2H, m), 3.4-3.9 (5H, m), 4.05-4.75 (4H,m), 6.48 (2H, m), 6.90-7.07 (5H, m) and 7.28 (2H, t).

Example 7 Synthesis of2-[[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-(4-phenoxyphenyl)amino]-N-(3-chlorobenzyl)acetamide(OGT4154)) Compound 12:((S)-1-{2-[[(3-Chlorobenzylcarbamoyl)methyl]-(4-phenoxyphenyl)amino]-acetyl}pyrrolidin-3-yl)-carbamicacid, tert-butyl ester

1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (144 mg, 0.75 mmol) wasadded to a solution of[[2-((S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(4-phenoxyphenyl)amino]aceticacid 20 (176 mg, 0.37 mmol), 1-hydroxy-7-azabenzotriazole (103 mg, 0.76mmol), 3-chlorobenzylamine (0.092 mL, 0.76 mmol) and N-methylmorpholine(0.11 mL, 1.02 mmol) in DMF (5 mL). The reaction mixture was stirredovernight at room temperature and then diluted with ethyl acetate andwashed with 10% hydrochloric acid (×2), brine, saturated aqueous sodiumbicarbonate (×2) and then brine, dried (Na₂SO₄) and evaporated ontosilica gel. Flash column chromatography, using ethyl acetate as theeluent, gave the title compound as a hard foam (159 mg, 71%). ¹HNMR (300MHz) (CDCl₃) δ 1.45 (6H, s), 1.55 (3H, s), 1.8-2.4 (2H, m), 3.35-3.90(5H, m), 3.95-4.40 (4H, m), 4.55-4.70 (2H, m), 6.48 (2H, m), 6.75-7.05(6H, m), 7.12 (3H, m), 7.25 (2H, m) and 9.81 (1H, m).

Compound 22

Trifluoroacetic acid (3 mL) was added to a solution of((S)-1-{2-[[(3-chloro-benzylcarbamoyl)methyl]-(4-phenoxyphenyl)amino]acetyl}-pyrrolidin-3-yl)-carbamicacid, tert-butyl ester 21 (70 mg, 0.1 mmol) in dichloromethane (9 mL).The reaction mixture was stirred at room temperature for 45 min, andthen concentrated in vacuo. The residue was dissolved in ethyl acetate,washed with 1M NaOH (×2), brine, dried (Na₂SO₄) and evaporated.Evaporation of the resultant residue from dichloromethane gave the titlecompound as a hard foam (74 mg, 64%). ¹HNMR (300 MHz) (d6-DMSO) δ1.5-2.1 (2H, m), 3.0-3.7 (5H, m), 4.05 (2H, br s), 4.25-4.40 (4H, m),6.47 (2H, m), 6.85 (2H, d), 6.93 (2H, d), 7.02 (1H, t), 7.06-7.13 (1H,m), 7.17 (1H, br s), 7.20-7.25 (2H, m), 7.25-7.35 (2H, m) and 9.95 (1H,m).

Example 8 Synthesis of2-[[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-(4-phenoxyphenyl)amino]-N-[3-fluoro-5-(trifluoromethyl)benzyl]acetamide(OGT4155) Compound 23:((S)-1-{2-[[(3-Fluoro-5-(trifluoromethyl)benzylcarbamoyl)methyl]-(4-phenoxy-phenyl)amino]acetyl}-pyrrolidin-3-yl)-carbamicacid, tert-butyl ester

1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (144 mg, 0.75 mmol) wasadded to a solution of[[2-((S)-3-butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(4-phenoxyphenyl)amino]aceticacid 20 (176 mg, 0.38 mmol), 1-hydroxy-7-azabenzotriazole (103 mg, 0.76mmol), 3-fluoro-5-(trifluoromethyl)benzylamine (0.11 mL, 0.75 mmol) andN-methylmorpholine (0.11 mL, 1.02 mmol) in DMF (5 mL). The reactionmixture was stirred overnight at room temperature and then diluted withethyl acetate and washed with 10% hydrochloric acid (×2), brine,saturated aqueous sodium bicarbonate (×2) and brine, dried (Na₂SO₄) andevaporated onto silica gel. Flash column chromatography, using ethylacetate as the eluent, gave the title compound as a hard foam (82 mg,34%). ¹HNMR (300 MHz) (CDCl₃) δ 1.45 (6H, s), 1.55 (3H, s), 1.75-2.40(2H, m), 3.37-3.93 (5H, m), 3.95-4.40 (4H, m), 4.50-4.70 (2H, m), 6.46(2H, m), 6.94 (4H, m), 7.03 (2H, m), 7.08 (1H, m), 7.30 (3H, m) and10.06 (1H, m).

Compound 24

Trifluoroacetic acid (3 mL) was added to a solution of((S)-1-{2-[[(3-fluoro-5-(trifluoromethyl)benzylcarbamoyl)methyl]-(4-phenoxy-phenyl)amino]acetyl}-pyrrolidin-3-yl)-carbamicacid, tert-butyl ester 23 (70 mg, 0.1 mmol) in dichloromethane (9 mL).The reaction mixture was stirred at room temperature for 45 min, andthen concentrated in vacuo. The residue was dissolved in ethyl acetate,washed with 1M NaOH (×2), brine, dried (Na₂SO₄) and evaporated todryness. The resultant residue was then evaporated from dichloromethaneto give the title compound as a hard foam (48 mg, 81%). ¹HNMR (300 MHz)(d6-DMSO) δ 1.5-2.1 (2H, m), 3.0-3.7 (5H, m), 4.07 (2H, br s), 4.30-4.50(4H, m), 6.48 (2H, m), 6.80-6.95 (4H, m), 7.02 (1H, t), 7.20-7.35 (3H,m), 7.40 (1H, s), 7.48 (1H, d) and 10.06 (1H, m).

Example 9 Synthesis of2-[[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxyphenyl)amino]-N-[3,5-bis-(trifluoromethyl)benzyl]acetamide(OGT4165) Compound 25 (Intermediate):[Carboxymethyl-(3-phenoxyphenyl)amino]acetic acid

Lithium hydroxide (4.06 g, 170 mmol) in water (50 mL) was added to asolution of [carboxymethyl-(3-phenoxyphenyl)amino]acetic acid,bis-methyl ester (11.18 g, 33.95 mmol) in THF (150 mL) and methanol (50mL). The reaction mixture was stirred at room temperature for 1 h,acidified to pH 1 with concentrated sulfuric acid and then concentratedin vacuo. The residue was extracted with ethyl acetate and the organiclayer washed with 10% hydrochloric acid, brine, dried (Na₂SO₄) andevaporated to dryness. The crude product was recrystallised from ethylacetate/petrol to give the title compound as a white solid (9.98 g,97%). ¹HNMR (300 MHz) (d6-DMSO) δ 6.18 (1H, br s), 4.08 (4H, s), 6.24(1H, dd), 6.30 (1H, dd), 6.97 (2H, d), 7.10 (1H, t), 7.15 (1H, t), 7.36(2H, t) and 12.7 (1H, br s).

Compound 26 (Intermediate): 4-(3-Phenoxyphenyl)morpholine-2,6-dione

[Carboxymethyl-(3-phenoxyphenyl)amino]acetic acid 25 (5 g) was heated atreflux in acetic anhydride (30 mL) for 1 h. The cooled reaction mixturewas poured into saturated aqueous sodium bicarbonate and extracted withethyl acetate. The organic layer was washed several times with saturatedaqueous sodium bicarbonate (until no further effervescence was observed)and twice with brine. The organic phase was dried (Na₂SO₄) andconcentrated in vacuo to give the title compound as a golden oil (4.7 g,100%). ¹HNMR (300 MHz) (CDCl₃) δ 6.10 (1H, m), 6.67 (2H, br d), 7.03(2H, d), 7.17 (1H, t), 7.30 (1H, t) and 7.39 (2H, t).

Compound 27 (Intermediate):[[2-((S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxy-phenyl)amino]aceticacid

To a solution of 4-(3-phenoxyphenyl)morpholine-2,6-dione 26 (4.7 g,0.0166 mol) in THF (50 mL) was added(3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (4.11 g, 0.0221 mol).The reaction mixture was stirred for 3 days after which time aprecipitate had formed. This material was collected by filtration, thenwashed with ethyl acetate to give the first crop of the title compound.A further crop was obtained by evaporating the filtrate in vacuo. Theresultant residue was dissolved in ethyl acetate, washed with 10%hydrochloric acid and brine, dried (Na₂SO₄) and concentrated in vacuo.The second crop of title compound which precipitated was collected byfiltration to give a total yield of 4.36 g (50%), as a cream solid.¹HNMR (300 MHz) (d6-DMSO, 100° C.)) δ 1.43 (9H, s), 1.75-2-20 (2H, 2×m),2.75-3.1 (1H, br), 3.20-3.75 (4H, m), 4.09 (2H, s), 4.21 (2H, s), 6.22(1H, br s), 6.37 2H, br t), 6.70 (1H, br), 6.99 (2H, d), 7.14 (2H, m)and 7.37 (2H, br t).

Compound 28 (Intermediate):[[2-((S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxy-phenyl)amino]aceticacid, pentafluorophenyl ester

To a solution of[[2-((S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxyphenyl)amino]aceticacid 27 (4.36 g, 9.39 mmol) in DMF (30 mL) were added pentafluorophenol(1.88 g, 10.21 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide(1.96 g, 10.22 mmol). The reaction mixture was stirred overnight at roomtemperature. It was then diluted with ethyl acetate, washed with 10%hydrochloric acid (×2), brine (×2), dried (Na₂SO₄) and concentrated invacuo. The resultant solid was evaporated twice from diethyl ether togive the title compound as a colourless, glassy solid (3.4 g, 57%) whichwas used directly in the next step.

Compound 29:((S)-1-{2-[[(3,5-bis-(Trifluoromethyl)benzylcarbamoyl)methyl]-(3-phenoxy-phenyl)amino]acetyl}-pyrrolidinyl-3-yl)-carbamicacid, tert-butyl ester

[[2-((S)-3-tert-Butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxy-phenyl)amino]aceticacid, pentafluorophenyl ester 28 (200 mg, 0.32 mmol),3,5-bis-(trifluoromethyl)benzylamine (115 mg, 0.47 mmol) and morpholineresin (190 mg, 2.5 mmol/g, 1.5 eq) in dichloromethane (5 mL) werestirred at room temperature for 2 h. Isocyanate resin (1.5 eq) was thenadded to remove residual amine and the reaction mixture was filtered.The filtrate was purified by silica gel chromatography, using ethylacetate/hexane (1:1) as eluent, to remove impurities followed bymethanol to provide the title compound which was used directly in thenext step. Compound 30:2-[[2-((S)-3-Aminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxyphenyl)amino]-N-[3,5-bis-(trifluoromethyl)benzyl]acetamide(OGT4165)

This compound was prepared from((S)-1-{2-[[(3,5-bis-(trifluoromethyl)benzyl-carbamoyl)methyl]-(3-phenoxyphenyl)amino]acetyl}pyrrolidin-3-yl)-carbamicacid, tert-butyl ester 29 by the same method as described for compound24. ¹HNMR (300 MHz) (d6-DMSO) δ 1.5-2.1 (2H, m), 3.0-3.6 (5H, m), 4.05(2H, m), 4.35 (2H, m), 4.50 (2H, m), 6.10 (1H, m), 6.24 (2H, m), 6.93(2H, d), 7.13 (2H, m), 7.34 (2H, t), 7.85 (2H, s), 7.94 (1H, s) and10.08 (1H, m).

Example 10

Compounds of the present invention can be made according to thefollowing scheme:

STEP 1: 2-Phenoxyaniline is heated with a slight excess of methylbromoacetate in DMF solvent in the presence of an excess of potassiumcarbonate and a catalytic amount of tetrabutylammonium iodide. Uponcomplete consumption of the starting material, the reaction mixture issubjected to an aqueous workup and product ester isolated by standardmethods.

STEP 2: Hydrolysis of the ester is performed by treatment with oneequivalent of LiOH in MeOH:THF:water/1:1:1 and heating the mixture toreflux until starting material is consumed. Treatment with oneequivalent of HCl followed by concentration affords the acid.

STEP 3: The acid is activated with a slight excess of DCC and a slightexcess of pentafluorophenol in methylene chloride solvent and theresulting pentafluorophenyl ester is treated with BOC-protected3-aminopyrrolidine. Upon complete consumption of the starting materialthe reaction mixture is subject to a basic pH aqueous workup and theproduct amide isolated by standard methods.

STEP 4: The aniline is treated with an excess of cinnamoyl chloride,HOBT and triethylamine in DCE and heated until starting material hasbeen consumed. At this time the reaction mixture is subject to aqueousworkup and the product isolated by standard means to afford the productamide.

STEP 5: The protected amine is treated with 0.1 equivalents oftrifluoroacetic acid in methylene chloride. Upon consumption of thestarting material the reaction mixture is poured into aqueous diluteNaOH and isolated by standard methods to provide the desired amine.

Example 11

Compounds of the present invention can be made according to thefollowing scheme:

STEP 1: Commercially available 2-phenoxyaniline is heated with a largeexcess of methyl bromoacetate in DMF solvent in the presence of anexcess of potassium carbonate and a catalytic amount oftetrabutylammonium iodide. Upon complete consumption of the startingmaterial, the reaction mixture is cooled to rt, concentrated to a thickslurry, the residue subjected to an aqueous workup and the product esterisolated by standard methods.

STEP 2: Hydrolysis of the ester is performed by treatment with twoequivalents of LiOH in MeOH:THF:water/1:1:1 and heating the mixture toreflux until starting material is consumed. Treatment with twoequivalents of HCl followed by concentration affords the diacid.

STEP 3: The diacid is dissolved in 20 equivalents of acetic anhydrideand heated to reflux for 3 h. After this time, the reaction mixture iscooled to rt and concentrated to dryness on a hi-vacuum rotaryevaporator. The reside is taken directly into the next step.

STEP 4: The cyclic anhydride is dissolved in THF and a slight excess of3-chlorobenzylamine is added. Upon consumption of the starting material,the reaction mixture is poured onto dilute aqueous HCl and extractedwith methylene chloride. The organic extracts are dried andconcentration to provide the acid-amide.

STEP 5: The acid-amide is activated with a slight excess of DCC and aslight excess of pentafluorophenol in methylene chloride solvent and theresulting pentafluorophenyl ester is treated with 3-aminopyrrolidine.Upon complete consumption of the starting material the reaction mixtureis subject to a basic pH aqueous workup and the product isolated bystandard methods.

Example 12

Additional examples can be prepared by substituting the BOC-protected3-aminopyrrolidine employed in any of the above examples with a suitablyprotected amine derived from the building blocks shown below:

Example 13

Additional examples can be prepared by substituting the cinnamoylchloride employed in any of the above examples with a suitable acidchloride derived from the simple esters prepared as shown below:

Example 14

Additional examples can be prepared by replacing the diphenyl etherillustrated in Schemes 1 and 4 with a substituted diphenyl ether anilinewherein the diphenyl ether moiety is constructed via the procedure ofBuck (Organic Syntheses (2005), Vol. 82, p. 69).

Example 15

The following compounds are synthesized by methods described herein orknown in the art using the appropriate starting materials, reagents,intermediates and protecting groups, when necessary.

Example 16

The following compounds are synthesized by methods described herein orknown in the art using the appropriate starting materials, reagents,intermediates and protecting groups, when necessary.

The following compounds were synthesized by methods described herein orknown in the art using the appropriate starting materials, reagents,intermediates and protecting groups, when necessary.

Example 18

The following compounds were synthesized by methods described herein orknown in the art using the appropriate starting materials, reagents,intermediates and protecting groups, when necessary.

Example 19

The following compounds were synthesized by methods described herein orknown in the art using the appropriate starting materials, reagents,intermediates and protecting groups, when necessary.

It should be understood that the above outlined processes are detailedsolely for the purpose of illustrating the invention and are notlimiting thereon. It will be appreciated by someone skilled in the artthat by using similar or analogous reagents and/or conditions in variouscombinations, it will be possible to synthesize other derivativesencompassed in the general Formula I. The activity and selectivity ofthe compounds produced may be determined by any suitable assay known inthe art.

It will also be appreciated that the chemical building blocks used inthe synthesis of compounds of general Formula I are either commerciallyavailable or can be synthesized by methods known in the art.

II. Biological Screening Example 1 Glucan Synthase Assay

The glucan synthase assay follows the incorporation of tritiatedUDP-glucose into acid insoluble β-glucan as catalysed by the glucansynthase activity present in membrane preparations from Candida albicansand Aspergillus fumigatus. UDP—[³H]-glucose (ca 0.01 μCi is added to 100μl assay buffer (50 mM Tris-C1, pH8.0, 8% glycerol, 1 mM EDTA, 1.5 mMKF, 1 mM DTT, 20 μM GTPγS, 600 μM UDP-glucose) and the reactioninitiated by the addition of 2.5 μl of enzyme preparation.

After incubation at 30° C. for 120 minutes, 10 μl of 30 mg/ml BSA isadded with mixing and the reaction is terminated with 110 μl ice-cold20% TCA. The precipitate is collected on a GF/B filter plate and washedthree times with 200 μl water. Once dry, 200 μl of Microscint20 is addedto each well and the plate is read on a Top-count scintillation counter.

Example 2 Proliferation Assay

Overnight cultures of organism were diluted back to an OD_(600nm) of 0.1in fresh media. Test compounds were added in a final concentration of0.5% DMSO and the OD_(600nm) was followed over 6 hours incubation at 25°C. Compounds described herein were screened to determine their activityas inhibitors of β-1,3-glucan synthase from Candida albicans andAspergillus fumigatus and for their ability to inhibit the growth ofCandida albicans and Aspergillus fumigatus whole organisms. Theactivities of various compounds described herein are shown in the Tablebelow.

A. C. albicans fumigatus Glucan Glucan C. A. Synth Synth albicansfumigatus Structure IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) OGT4325

8.5 15.6 8 NT OGT4355

15 23 18  4 OGT4344

34 49 27 12 OGT4165

2.7 6.2 19 43 OGT4154

8 5.6 22 12 OGT4155

5.4 5.2 17 14 OGT3935

12 38 55 93 NT: not tested

Example 3 Glucan Biosynthesis Assay

This procedure confirms the specificity of the effects of the inhibitorsby simultaneously following the incorporation of labelled acetate intofatty acids, and glucose into β-glucans in growing cultures of Candida.The fatty acids are extracted into solvent, and the glucan is releasedby treatment with β-glucanase preparations.

A 10 ml culture of Candida was grown in YPD media overnight at 30° C.The culture was diluted to 10⁷ cells/ml in 1 ml aliquots and continuedto grow for a further 2 hours prior to the addition of test compound(Caspofungin—20 ng/ml, Cerulenin—10 μg/ml). After 30 min 1 μCi of eachof ¹⁴C-glucose, ¹⁴C-acetate and ³H—N-acetyl-glucosamine were added.After a further 30 min, 500 μl of unlabelled ‘carrier cells’ from theovernight culture were added and the cells spun down and transferred toice. Following 3 washes in ice-cold PBS, 250 μl of glass beads wereadded and the cells broken by 1 min shaking in a bead-beater.

For acetate labelling, the homogenate was extracted for 1 hour with anequal volume of choroform:methanol (1:1). The organic layer was washedwith water and 50 μl was removed to 2 ml scintillant for counting.

For glucose labelling, the cell-wall pellet was washed (spun at 16000 gfor 2 min) 3 times in 5% NaCl, and 3 times in 1 mM EDTA. The pellet wasresuspended in 200 μl 10 mM Na₂PO₄, pH7.5/150 mM NaCl/5 mM EDTA/2 mM DTTcontaining 5 μl of Quantazyme. After an overnight incubation at roomtemperature a sample of the solubilised label was added to scintillantand counted.

FIG. 1 shows the inhibition of glucose incorporation into β-1,3-D-glucanin Candida Albicans strain CAF2-1. OGT4154 preferentially inhibitsβ-1,3-D-glucan biosynthesis in Candida Albicans.

Example 4 Evaluation of OGT 4154 in an Animal Model

Six-week-old, specific pathogen-free female Swiss ICR(CD1) mice arehoused in groups of five per cage and allowed free access to food andwater to acclimate 7 days before the initiation of experiments. At thetime of the study, the animals weigh 23-27 g.

In order to mimic the immunocompromised state common to many subjects athigh risk of a fungal infection, a profound state of granulocytopenia isproduced in animals to maximize the growth of Candida in the mice. Thisimmuno-compromised state is achieved by administration ofcyclophosphamide to the mice prior to infection. Cyclophosphamide isadministered via intraperitoneal injection four days (150 mg/kg) and oneday (100 mg/kg) before the day of infection. The degree and duration ofneutropenia is confirmed by monitoring neutrophil counts of peripheralblood smears with a hemocytometer daily throughout the duration of thestudy.

In order to initiate the Candida infection, neutropenic mice are placedhead first into a mouse restraint device with the tail extending freelyhanging through the other end. The tail is immersed in warm (50° C.)water bath for 5-10 s to dilate the veins. Using a (1 mL) tuberculinsyringe with either a 26- or 27-gauge needle the inoculum (0.1 mL of asuspension of 10⁵⁻⁷ CFU/mL Candida blastospores) is injected via thelateral tail vein. The animals are monitored at least every six hoursafter infection for the remainder of the study period.

Pharmacokinetic Studies

Three groups of six animals (corresponding to three dose regimens) areadministered a compound of Formula I by oral gavage at a dose of 0.1,0.5, or 3 mg/kg. Afterwards, blood is sampled at 1, 3, 6, 12, 18, 24,and 36 hours post-administration. Blood from groups of three mice issampled at each sampling time point. At the next time point the secondgroup of three mice is sampled. Thus, any one mouse is sampled onlythree or four times to minimize the impact of blood loss on drugconcentrations. Before sampling, the animals are anesthetized with a fewdrops of halothane on a bell jar. Blood (50 μL per time point) iscollected in heparinized capillary tubes (Fisher Scientific, Pittsburg,Pa.) from the orbital venous plexus. The volume of blood collected formany individual animal is less then 5% of the total blood volume.

The tubes are immediately centrifuged in a capillary centrifuge at10,000×g for 4-5 minutes, the serum is removed with a micropipet, placedin the wells of a 96-well microtiter plate and frozen at −80° C. untilthe assay for OGT 4154 is performed.

Levels of the compound in each sample are then evaluated by HPLC. Anassay of six to eight standards of drug-spiked serum (twofold escalatingconcentrations) to create a standard curve is similarly assayed. Thelower limit of detection for the assay is defined, and the intra- andinterday variation calculated. Pharmacokinetic constants for each drugdose level are calculated using the drug concentrations from theindividual mouse samples. The elimination half-life in thepostdistributive phase is calculated using a noncompartment model and anunweighted least linear squares method. The AUC is calculated using thelinear trapezoidal rule up to the final measured concentration and thenextrapolated to infinity.

Analysis of Binding to Serum Protein

Since serum protein binding of anti-infective drugs can reduceantimicrobial activity, restrict tissue distribution, and delay drugelimination, protein-binding studies of a compound of Formula I areperformed on the serum of neutropenic mice using an ultrafiltrationmethod. After the mouse serum samples are spiked with a series of drugconcentrations, one mL aliquots is filtered by centrifugation throughMillipore YM10 filter device (10,000 MW exclusion) (Millipore Corp.Bedford, Mass. using a fixed angle rotor at 5000×g for five minutes. Theconcentration of OGT 4154 in serum and in ultrafiltrate to determine thedegree of protein binding at each of the drug concentrations, where thepercentage of protein bound drug is calculated as:

% Protein Bound Drug=([Serum]−[Ultrafiltrate])/[Serum]×100

Evaluation of Therapeutic Efficacy in Neutropenic Mice

A compound of Formula I at escalating doses (10-100 mg/kg) or vehicleare administered to neutropenic mice by oral gavage two hours afterinfection with Candida as described above. This delay after infectionallows the cells to enter the early log phase of growth in the mousekidneys. Antifungal efficacy is assessed by comparison to themicrobiological clearance of Candida from kidneys in treated vsuntreated control mice. At the end of therapy, animals are euthanized byCO₂ asphyxiation. Both kidneys are aseptically removed and placed in 3.4ml of sterile cold 0.9% NaCl (an initial 1-10 dilution based on weightof kidneys). The kidney tissue is then homogenized using a Polytronhomogenizer for 20 seconds. After homogenization of each tube, thegrinder bit is washed with 70% ethanol followed by fresh tap water. Thismethod prevents significant organism carryover from sample to sample.

Each tissue homogenate is then serially diluted 10-fold from 1/10 to1/10⁶ in sterile 0.9% NaCl.

The dilutions are plated in duplicated on SD agar plates fordetermination of viable fungal colony counts after incubation at 37° C.for 24 hours.

Colony counts are expressed as the mean±standard deviation log₁₀CFU/kidney. Previous studies with this series of dilutions havedemonstrated that the method is sensitive to detection of 100CFU/kidneys.

Example 5 Human Clinical Trial of Safety

Objective: To determine the safety and pharmacokinetics of orallyadministered a compound of Formula I.

Clinical Trial Participants

Thirty healthy volunteers ranging between 20-40 years of age andweighing between 60-90 kg are enrolled in the study. The subjects willhave no clinically significant abnormal laboratory values for hematologyor serum chemistry, and a negative urine toxicology screen, HIV screen,and hepatitis B surface antigen screen. They should not have anyevidence of the following: hypertension; a history of any primaryhematologic disease; history of significant hepatic, renal,cardiovascular, gastrointestinal, genitourinary, metabolic, neurologicdisease; habitual and heavy consumption of beverages containingcaffeine; participation in any other clinical trial or had bloodtransfused or donated within 30 days of study entry; or have significantabnormalities on the pre-study physical examination or the clinicallaboratory evaluations within 14 days of study entry. All subjects areevaluated for safety and all blood collections of pharmacokineticanalysis are collected as scheduled. All studies are performed withinstitutional ethics committee approval and patient consent.

Study Design This is a Phase I, single center, open label, randomizedstudy in healthy male volunteers. Thirty subjects are randomly assignedto one of three dosing groups (0.2, 0.5, or 1.5 mg/kg). A compound ofFormula I is administered orally. Additional dosing, dosing frequency,or other parameter may be added to the study as desired by includingadditional groups of subjects. Subjects are confined to the study centerfor at least 12 hours prior to and 72 hours following dosing for thestudy period.

Blood Sampling Serial blood is drawn by direct vein puncture before andafter administration of a compound of Formula I. Venous blood samples (5mL) for determination of serum concentrations of the compound of FormulaI are obtained at about 20 minutes prior to dosing (baseline sample) andat 1, 2, 5, 8, 12, 15, 18, 24, 30, 36, 48, 60, and 72 hours afterdosing. Each serum sample is divided into two aliquots. All serumsamples are stored at −20° C. Serum samples are shipped on dry ice.Fasting clinical laboratory tests (hematology, serum chemistry, andurinanalysis) are performed immediately prior to dosing, the morning ofday 4 following dosing, and the morning of day 7 following dosing.

Bioanalytical Methods An HPLC assay is used to determine serumconcentrations of a compound of Formula I.

Safety Determinations Vital signs are recorded immediately prior todosing, and at 6, 24, 48, and 72 hours after each dosing. Safetydeterminations are based on the incidence and type of adverse events andthe changes in clinical laboratory tests from baseline. In addition,changes from pre-study vital sign measurements, including bloodpressure, and physical examination results are evaluated.

Data Analysis Pharmacokinetic parameters are calculated by modelindependent methods using the latest version of the BIOAVL software. Thefollowing pharmacokinetic parameters are determined: peak serumconcentration (C_(max)); time to peak serum concentration (t_(max));area under the concentration-time curve (AUC) from time zero to the lastblood sampling time (AUC₀₋₇₂) calculated with the use of the lineartrapezoidal rule; estimated by linear regression of consecutive datapoints in the terminal linear region of the log-linearconcentration-time plot. The mean, standard deviation (SD), andcoefficient of variation (CV) of the pharmacokinetic parameters arecalculated for each treatment.

III. Pharmaceutical Compositions Example 1a Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of anycompound of Formula I, is dissolved in DMSO and then mixed with 10 mL of0.9% sterile saline. The mixture is incorporated into a dosage unit formsuitable for administration by injection.

Example 1b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of anycompound of Formula I, is mixed with 750 mg of starch. The mixture isincorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

Example 1c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of any compound of Formula I, with 420 mg ofpowdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilledwater, and 0.42 mL mint extract. The mixture is gently blended andpoured into a mold to form a lozenge suitable for buccal administration.

Example 1d Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof any compound of Formula I, is mixed with 50 mg of anhydrous citricacid and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Example 1e Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg ofany compound of Formula I, is mixed with 2.5 g of methylcelluose (1500mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purifiedwater. The resulting gel mixture is then incorporated into rectaldelivery units, such as syringes, which are suitable for rectaladministration.

Example 1f Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of anycompound of Formula I, is mixed with 1.75 g of hydroxypropyl celluose,10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL ofpurified alcohol USP. The resulting gel mixture is then incorporatedinto containers, such as tubes, which are suitable for topicladministration.

Example 1g Ophthalmic Solution Composition

To prepare a pharmaceutical opthalmic solution composition, 100 mg ofany compound of Formula I, is mixed with 0.9 g of NaCl in 100 mL ofpurified water and filterd using a 0.2 micron filter. The resultingisotonic solution is then incorporated into ophthalmic delivery units,such as eye drop containers, which are suitable for ophthalmicadministration.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims. All publications,patents, and patent applications cited herein are hereby incorporated byreference for all purposes.

1-22. (canceled)
 23. A method for treating a subject at risk of or suffering from a fungal infection, the method comprising administering to the subject a composition comprising a therapeutically effective amount of the compound having the structure of Formula I:

wherein, n is 0, 1, or 2; R₁ and R₂ are independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₁-C₆)heteroalkyl, (C₁-C₆)heteroalkenyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, (C₃-C₈)heterocycloalkyl, (C₃-C₈)heterocycloalkenyl, aryl, and heteroaryl each of which is optionally substituted with 1 or 2 independently selected R_(x) groups; or R₁ and R₂ together with the nitrogen atom to which they are attached form a 4-to 8-membered heterocycloalkyl or heterocycloalkenyl group each of which is optionally substituted with 1 or 2 independently selected R_(x) groups; Ar is selected from phenyl, naphthyl, and a monocylic or bicyclic heteroaryl group, each of which is optionally substituted with 1 or 2 independently selected R_(x) groups, or with a phenyl, O-phenyl, or OCH₂-phenyl in which the phenyl group of each is optionally substituted with 1 or 2 independently selected R_(x) groups; R₃ is L₁-L₂-R₄, where L₁ is selected from a bond, O, NR₁, and S; L₂ is selected from a bond, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₁-C₆)heteroalkyl, (C₁-C₆)heteroalkenyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, (C₃-C₈)heterocycloalkyl, and (C₃-C₈)heterocycloalkenyl; and R₄ is selected from H, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl each of which is optionally substituted with 1 or 2 independently selected R_(x) groups; R_(x) is L_(s1)L_(s2)R_(s), wherein each L_(s1) and L_(s2) is independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(O)NH—, —NHC(O)O—, (C₁-C₆) alkyl, and —(C₂-C₆) alkenyl; and R_(s) is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, silyl, and amino, including mono- and di-substituted amino groups; or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer, isomer, or an active metabolite thereof.
 24. The method of claim 23 comprising administering to the subject a composition comprising a therapeutically effective amount of the compound having the structure of Formula I wherein n is 0 or
 1. 25. The method of claim 24 wherein n is
 0. 26. The method of claim 23 comprising administering to the subject a composition comprising a therapeutically effective amount of the compound of Formula I wherein R₁ and R₂ together with the nitrogen atom to which they are attached form a heterocycloalkyl group selected from:

wherein: each NH₂ group is optionally substituted with a C₁-C₆ alkyl group; X is O, NR or SO₂, and each R is independently selected from halogen, —OH, —NH₂, —SH, —S(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ heteroalkyl.
 27. The method of claim 23 comprising administering to the subject a composition comprising a therapeutically effective amount of the compound of Formula I wherein Ar is phenyl that is substituted with OCH₂-phenyl which is optionally substituted with 1 or 2 independently selected R_(x) groups.
 28. The method of claim 23 comprising administering to the subject a composition comprising a therapeutically effective amount of the compound of Formula I wherein L₁ is a bond.
 29. The method of claim 23 comprising administering to the subject a composition comprising a therapeutically effective amount of the compound of Formula I wherein L₂ is (C₂-C₆)alkenyl that is optionally substituted with 1 or 2 independently selected R_(x) groups.
 30. The method of claim 23 comprising administering to the subject a composition comprising a therapeutically effective amount of the compound of Formula I wherein L₂ is (C₂-C₆)alkynyl that is optionally substituted with 1 or 2 independently selected R_(x) groups.
 31. The method of claim 23 comprising administering to the subject a composition comprising a therapeutically effective amount of the compound of Formula I wherein R₄ is aryl that is optionally substituted with 1 or 2 independently selected R_(x) groups.
 32. The method of claim 23 comprising administering to the subject a composition comprising a therapeutically effective amount of the compound of Formula I wherein R₁ and R₂ together with the nitrogen atom to which they are attached form a 5-8 membered heterocycloalkyl or heterocycloalkenyl group.
 33. The method of claim 23 comprising administering to the subject the composition that further comprises a pharmaceutically acceptable diluent or carrier.
 34. The method of claim 23 wherein the fungal infection is caused at least in part by a fungus of the Candida or Apergillus genera.
 35. The method of claim 34 wherein the fungal infection is caused at least in part by Candida albicans or Aspergillus fumigatus.
 36. The method of claim 35 wherein the fungal infection is caused at least in part by Candida albicans.
 37. The method of claim 35 wherein the fungal infection is caused at least in part by Aspergillus fumigatus.
 38. The method of claim 23 wherein the subject is diagnosed as suffering from blastomycosis, tinea, coccidiomycosis, cryptococcosis, candidiasis, moniliasis, dermatomycosis, dermatophytosis, favus, keratomycosis, phycomycosis, sporotrichosis, or rhinosporidiosis.
 39. The method of claim 23 wherein the subject is immunocompromised or is undergoing immunosuppressive therapy.
 40. The method of claim 39 wherein the subject is suffering from or the fungal infection is caused by AIDS, cancer, severe combined immunodefficiency, tuberculosis, diabetes, intravenous drug abuse, or severe burns.
 41. The method of claim 23 wherein the administration is oral, topical, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular, intranasal, rectal, vaginal, buccal, or sublingual.
 42. The method of claim 23 wherein the composition is administered as an ingestible tablet, a buccal tablet, a troche, a capsule, an elixir, a suspension, a syrup, a wafer, a cream, an ointment, a paste, a gel, a spray, or a liposomal preparation. 